JP2009511478A - Pyrazolopyrimidines as protein kinase inhibitors - Google Patents

Abstract

In many embodiments of the invention, the present invention provides a novel class of pyrazolo [1,5-a] pyrimidine compounds as inhibitors of protein kinases and / or checkpoint kinases, methods for preparing such compounds, 1 Pharmaceutical compositions comprising one or more such compounds, methods for preparing pharmaceutical formulations comprising one or more such compounds, and protein kinases or the like using such compounds or pharmaceutical compositions Methods of treating, preventing, inhibiting or ameliorating one or more diseases associated with checkpoint kinases are provided.

Description

(Field of Invention)
The present invention relates to substituted pyrazolo [1,5-a] pyrimidine compounds useful as inhibitors, modulators or modulators of protein kinases, pharmaceutical compositions containing the compounds, and diseases (eg, cancer, inflammation, arthritis, viral It relates to methods of treatment using the compounds and compositions to treat diseases, neurodegenerative diseases (eg Alzheimer's disease), cardiovascular diseases and fungal diseases. This application claims priority from US Provisional Patent Application No. 60 / 724,159, filed Oct. 6, 2005.

(Background of the Invention)
Protein kinases are a family of enzymes that catalyze the phosphorylation of proteins, particularly the hydroxyl groups of specific tyrosine, serine or threonine residues in proteins. Protein kinases are important in the regulation of a wide range of cellular processes, including metabolism, cell proliferation, cell differentiation and cell survival. Uncontrolled proliferation is a characteristic of cancer cells, and is due to deregulation of the cell division cycle in one of two ways (overacting a stimulating gene or inactivating an inhibitory gene). Can appear. Protein kinase inhibitors, modulators or modulators include kinases such as cyclin dependent kinases (CDK), mitogen activated protein kinases (MAPK / ERK), glycogen synthase kinase 3 (GSK3β), Chk kinase, AKT kinase, etc. Change function. Examples of protein kinase inhibitors are described in WO 02/22610 A1 and in Y.W. Mettey et al. Med. Chem. (2003) 46 222-236.

  Cyclin-dependent kinases are serine / threonine protein kinases, which are driving forces that support the cell cycle and cell growth. In many important solid tumors, misregulation of CDK function occurs frequently. Individual CDKs (eg, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6 and CDK7, CDK8, etc.) play different roles in cell cycle progression, which are either G1 phase enzymes, S phase enzymes or G2M phase enzymes. It can be classified as either. CDK2 and CDK4 are particularly important because their activity is often misregulated in a wide variety of human cancers. CDK2 activity is required for progression from the G1 to S phase of the cell cycle, and CDK2 is one of the key elements of the G1 checkpoint. While checkpoints serve to maintain a proper chain of cell cycle events and allow cells to respond to injury or proliferation signals, loss of proper checkpoint control in cancer cells It will contribute. This CDK2 pathway affects tumorigenesis at the level of tumor suppressor functions (eg, p52, RB and p27) and oncogene activation (cyclin E). Many reports of CDK2 coactivators (cyclin E) and inhibitors (p27) in breast cancer, colon cancer, non-small cell lung cancer, gastric cancer, prostate cancer, bladder cancer, non-Hodgkin lymphoma, ovarian cancer and other cancers. Both demonstrate over- or under-expression, respectively. These altered expression has been shown to correlate with elevated CDK2 activity levels and poor overall survival. This observation has made CDK2 and its regulatory pathways an attractive target for the development of cancer therapeutics.

  Many adenosine 5'-triphosphate (ATP) competitive organic small molecules as well as adenosine 5'-triphosphate (ATP) competitive peptides have been reported in the literature as CDK inhibitors for potential treatment of cancer Has been. US Pat. No. 6,413,974, columns 1, 23-column 15, line 10 provides a thorough explanation of these relationships with various CDKs and various types of cancer. Flavopyridol (shown below) is a non-selective CDK inhibitor currently undergoing human clinical trials (AM Sanderovicz et al., J. Clin. Oncol. (1998) 16, 2986. 2999).

ＣＤＫの他の公知のインヒビターとしては、例えば、オロムチン（ｏｌｏｍｕｃｉｎｅ）（Ｊ． Ｖｅｓｅｌｙら、Ｅｕｒ． Ｊ． Ｂｉｏｃｈｅｍ．、（１９９４）２２４、７７１−７８６）およびロスコビチン（ｒｏｓｃｏｖｉｔｉｎｅ）（Ｉ． Ｍｅｉｊｅｒら、Ｅｕｒ． Ｊ． Ｂｉｏｃｈｅｍ．、（１９９７）２４３、５２７−５３６）が挙げられる。特許文献１は、ＣＤＫインヒビターとしての特定のピラゾロ［３，４−ｂ］ピリジン化合物を記載している。特許文献１からの例示的な化合物は、

Other known inhibitors of CDK include, for example, olomucine (J. Vesery et al., Eur. J. Biochem., (1994) 224, 771-786) and roscovitine (I. Meijer et al., Eur J. Biochem., (1997) 243, 527-536). Patent Document 1 describes specific pyrazolo [3,4-b] pyridine compounds as CDK inhibitors. Exemplary compounds from US Pat.

である。Ｋ． Ｓ． Ｋｉｍら、Ｊ． Ｍｅｄ． Ｃｈｅｍ． ４５（２００２）３９０５−３９２７およびＷＯ ０２／１０１６２は、ＣＤＫインヒビターとしての特定のアミノチアゾール化合物を開示している。

It is. K. S. Kim et al. Med. Chem. 45 (2002) 3905-3927 and WO 02/10162 disclose certain aminothiazole compounds as CDK inhibitors.

  Pyrazolopyrimidines are known. For example, Patent Literature 2, Patent Literature 3, Patent Literature 4, Patent Literature 5, EP 94304104.6, Patent Literature 6 (equivalent to Patent Literature 7, Patent Literature 8, and Patent Literature 9), Patent Literature 10, Chem. Pharm. Bull. (1999) 47 928, J. et al. Med. Chem. (1977) 20, 296, J. MoI. Med. Chem. (1976) 19 517 and Chem. Pharm. Bull. (1962) 10 620 discloses various pyrazolopyrimidines. Other publications of interest include Patent Document 11 and Patent Document 12, Patent Document 13, Patent Document 14, Patent Document 15, Patent Document 16, and DE 10223917.

  Another family of protein kinases plays an important role as a checkpoint in cell cycle progression. Checkpoints prevent cell cycle progression at an inappropriate time (eg, in response to DNA damage) and maintain the metabolic balance of the cell while it is stopped, in some instances, If the checkpoint requirement is not met, apoptosis (programmed cell death) can be induced. Checkpoint control can occur in the G1 phase (before DNA synthesis) and G2 phase (before entering mitosis).

Block one sequence of a series of checkpoints, genomic integrity monitoring, upon sensing damage DNA, these "DNA damage checkpoints" block cell cycle progression in G ₁ and G ₂ phases And slow down the progression during S phase. This action allows the process of DNA repair to complete these functions prior to genome replication and subsequent segregation of the genetic material into new daughter cells. Inactivation of CHK1 has been shown to transduce signals from the DNA damage sensing complex and inhibit the activity of cyclin B / Cdc2 kinase, which promotes entry into mitosis, and abolished stop G ₂ induced by DNA damage made by either DNA damage anticancer agents or endogenous, in addition, cause preferential killing checkpoint deficient cells resulting. For example, Peng et al., Science, 277, 1501-1505 (1997); Sanchez et al., Science, 277, 1497-1501 (1997), Nurse, Cell, 91, 865-867 (1997); Weinert, Science, 277, 1450. -1451 (1997); Walworth et al., Nature, 363, 368-371 (1993); and Al-Khodairy et al., Molec. Biol. Cell. 5, 147-160 (1994).

  Selective manipulation of checkpoint control in cancer cells can lead to widespread use in cancer chemotherapy and radiotherapy regimens, and in addition, human cancer "used as a selective basis for cancer cell destruction" It may provide a common feature of “genomic instability”. Many factors place CHK1 as an important target in DNA-damage checkpoint control. Description of inhibitors of CHK1 and functionally related kinases (eg CDS1 / CHK2 (a kinase recently discovered to cooperate with CHK1 in regulating S phase progression)) Reference 2) may provide a valuable new therapeutic entity for the treatment of cancer.

  Another group of kinases are tyrosine kinases. A tyrosine kinase can be a receptor type (having an extracellular domain, a transmembrane domain, and an intracellular domain) or a non-receptor type (completely intracellular). Receptor-type tyrosine kinases have numerous transmembrane receptors with diverse biological activities. In fact, approximately 20 different subfamilies of receptor-type tyrosine kinases have been identified. One tyrosine kinase subfamily (designated HER subfamily) includes EGER (HER1), HER2, HER3 and HER4. The ligands of this subfamily of receptors currently identified include epidermal growth factor, TGF-α, amphiregulin, HB-EGF, betacellulin, and heregulin. Another subfamily of tyrosine kinases of these receptor types is the insulin subfamily, including INS-R, IGF-IR, IR and IR-R. The PDGF subfamily includes PDGF-α and β receptors, CSFIR, c-kit and FLK-II. The FLK family includes kinase insert domain receptors (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and fms-like tyrosine kinase-1 (flt-1 )including. For a detailed discussion of this receptor type tyrosine kinase, see Plowman et al., DN & P 7 (6): 334-339, 1994.

  At least one of the non-receptor protein tyrosine kinases (ie, LCK) is thought to mediate signal transduction from the interaction of cell surface proteins (Cd4) with cross-linked anti-Cd4 antibodies in T cells. ing. A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, Oncogene, 8, 2025-2031 (1993). Non-receptor types of tyrosine kinases also include many subfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack and LIMK. Each of these subfamilies is further subdivided into various receptors. For example, the Src subfamily is one of the largest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes has been linked to tumorigenesis. For a more detailed discussion of non-receptor types of tyrosine kinases, see Bolen, Oncogene, 8, 2025-2031 (1993).

  In addition to its role in cell cycle control, protein kinases also play a vital role in angiogenesis, the mechanism by which new capillaries are formed from existing vessels. As needed, the vascular system has the potential to create new capillary networks to maintain the proper functioning of tissues and organs. However, in adults, angiogenesis is fairly limited and occurs only in the process of wound healing and endometrial neovascularization during menstruation. On the other hand, unwanted angiogenesis is characteristic of several diseases such as retinopathy, psoriasis, rheumatoid arthritis, age-related macular degeneration and cancer (solid tumors). Protein kinases that have been shown to be involved in the angiogenic process are three members of the growth factor receptor tyrosine kinase family (VEGF-R2 (vascular endothelial growth factor receptor 2, KDR (kinase insert domain receptor) and FGF-R (fibroblast growth factor receptor); and TEK (also known as Tie-2)).

  VEGF-R2 (which is expressed only on endothelial cells) binds to VEGF, a potent angiogenic growth factor, and subsequently signals through activation of its intracellular kinase activity. Mediate. Thus, as demonstrated by mutants of VEGF-R2 that cannot mediate signal transduction, direct inhibition of VEGF-R2 kinase activity is angiogenesis even in the presence of exogenous VEGF. (See Strawn et al., Cancer Research 56, 3540-3545 (1996)). Millauer et al., Cancer Research, 56, 1615-1620 (1996). Furthermore, VEGF-R2 does not appear to have any function in adults other than to mediate VEGF's angiogenic activity. Therefore, selective inhibitors of VEGF-R2 kinase activity are expected to show little toxicity.

  Similarly, FGFR binds to angiogenic growth factors (aFGF and bFGF) and mediates subsequent intracellular signaling. It has recently been suggested that growth factors (eg, bFGF) may play a crucial role in inducing angiogenesis in solid tumors that have reached a certain size. Yoshiji et al., Cancer Research, 57, 3924-3928 (1997). However, unlike VEGF-R2, FGF-R is expressed in many different cell types throughout the body and may or may not play an important role in other normal physiological processes in adults. Absent. Nevertheless, systemic administration of small molecule inhibitors of kinase activity of FGF-R has been reported to block bFGF-induced angiogenesis in mice without obvious toxicity. Mohammad et al., EMBO Journal, 17, 5996-5904 (1998).

TEK (also known as Tie-2) is another receptor tyrosine kinase that is expressed only on endothelial cells, which has been shown to play a role in angiogenesis. The binding of the factor angiopoietin-1 causes autophosphorylation of the kinase domain of TEK and leads to a signal transduction process that involves endothelial cells and peri-endothelial support cells. It seems to mediate the interaction of and thus promote the maturation of newly formed blood vessels. On the other hand, the factor angiopoietin-2 appears to antagonize the action of angiopoietin-1 on TEK and disrupt angiogenesis. Maisonpierre et al., Science, 277, 55-60 (1997).
Pim-1 is a small serine / threonine kinase. Elevated expression levels of Pim-1 have been detected in lymphoid and myeloid malignancies, and recently Pim-1 has been identified as a prognostic marker in prostate cancer. K. Peltola, “Signaling in Cancer: Pim-1 Kinases and its Partners”, Analyzes Universality Turkuensis, Sarja-Ser. D Osa-Tom. 616, (August 30, 2005), http: // kirjasto. utu. fi / julkaisupalvelut / annaalit / 2004 / D616. html. Pim-1 acts as a cell survival factor and can prevent apoptosis in malignant cells. K. Petersen Shay et al., Molecular Cancer Research 3: 170-181 (2005).
US Pat. No. 6,107,305 International Publication No. 92/18504 Pamphlet International Publication No. 02/50079 Pamphlet WO95 / 35298 pamphlet International Publication No. 02/40485 Pamphlet European Patent No. 0628559 US Pat. No. 5,602,136 US Pat. No. 5,602,137 US Pat. No. 5,571,813 US Pat. No. 6,383,790 US Pat. No. 5,688,949 US Pat. No. 6,313,124 International Publication No. 98/54093 Pamphlet International Publication No. 03/109933 Pamphlet International Publication No. 03/091256 Pamphlet International Publication No. 04/089416 Pamphlet Zeng et al., Nature, 395, 507-510 (1998). Matsuoka, Science, 282, 1893-1897 (1998).

  There is a need for effective inhibitors of protein kinases to treat or prevent disease states associated with abnormal cell proliferation. Furthermore, it is desirable for kinase inhibitors to have both high affinity for the target kinase as well as high selectivity for other protein kinases. Small molecules that can be readily synthesized and are potent inhibitors of cell proliferation include, for example, one or more protein kinases (eg, CHK1, CHK2, VEGF, CDK or CDK / cyclin complexes and both receptors and non-receptors) Tyrosine kinase).

(Summary of the Invention)
In many embodiments of the invention, the invention provides a substituted pyrazolo [1,5-a] pyrimidine compound, a method of preparing such a compound, a pharmaceutical composition comprising one or more such compounds, 1 Methods for preparing pharmaceutical formulations comprising two or more such compounds, and the treatment, prevention, inhibition or amelioration of one or more diseases associated with protein kinases using such compounds or pharmaceutical compositions Provide a way.

  In one aspect, the present invention provides structural formula (I):

によって表わされる化合物、またはこの式（Ｉ）の化合物の薬学的に受容可能な塩、溶媒和物、エステルもしくはプロドラッグを提供し、
ここで：
Ｒ^２は、Ｈ、アルキル、シクロアルキル、シクロアルキルアルキル、ハロアルキル、アルケニル、アルキニル、アルケニルアルキル、アルキニルアルキル、ヘテロシクリル、ヘテロシクロアルキル、トリフルオロメチル、ハロ、−ＣＮ、−ＯＣＦ_３、−ＣＯ_２Ｒ^８、−ＣＯＮＲ^８Ｒ^９、−ＯＲ^８ａ、−ＳＲ^８、−ＳＯ_２Ｒ^８、−ＳＯ_２ＮＲ^８Ｒ^９、−ＮＲ^８ＳＯ_２Ｒ^９、−ＮＲ^８ＣＯＲ^９および−ＮＲ^８ＣＯＮＲ^８Ｒ^９からなる群より選択され；
Ｒ^３は、ハロアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、シクロアルキル、シクロアルキルアルキル、アルケニルアルキル、アルキニルアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアリールアルキル、−ＮＲ^５Ｒ^８ａ、−ＮＲ^８ＣＯＲ^９、−ＮＲ^８ＳＯ_２Ｒ^９、−ＣＯＲ^８、−ＣＯ_２Ｒ^８、−ＣＯＮＲ^８Ｒ^９、−ＣＨ_２ＯＲ^８、−ＯＲ^８ｂ、−ＳＲ^８、−ＳＯ_２Ｒ^８、−Ｓ（Ｏ_２）ＮＲ^８Ｒ^９、−Ｓ（Ｏ_２）アリール、−Ｓ（Ｏ_２）ヘテロアリール、−Ｃ（Ｏ）ＮＲ^８Ｒ^９、−Ｃ（Ｏ）ＯＲ^９、−Ｃ（Ｏ）アリール、−Ｃ（Ｏ）ヘテロアリール、−（ＣＨＲ^５）_ｎ−アリール、−（ＣＨＲ^５）_ｎ−ヘテロアリール、

Or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound of formula (I),
here:
R ² is H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocycloalkyl, trifluoromethyl, halo, —CN, —OCF ₃ , —CO ₂ R ⁸ , -CONR ⁸ R ⁹ , -OR ^8a , -SR ⁸ , -SO ₂ R ⁸ , -SO ₂ NR ⁸ R ⁹ , -NR ⁸ SO ₂ R ⁹ , -NR ⁸ COR ⁹ and -NR ⁸ CONR ⁸ R Selected from the group consisting of ⁹ ;
R ³ is haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —NR ⁵ R ^8a , — _{^{NR 8 COR 9, -NR 8 SO}} 2 R 9, -COR 8, -CO 2 R 8, -CONR 8 R 9, -CH 2 OR 8, -OR 8b, -SR 8, -SO 2 R 8, - S (O ₂ ) NR ⁸ R ⁹ , —S (O ₂ ) aryl, —S (O ₂ ) heteroaryl, —C (O) NR ⁸ R ⁹ , —C (O) OR ⁹ , —C (O) Aryl, —C (O) heteroaryl, — (CHR ⁵ ) _n -aryl, — (CHR ⁵ ) _n -heteroaryl,

からなる群より選択され、ここで、Ｒ^３に関して上に示したアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、シクロアルキル、シクロアルキルアルキル、アルケニルアルキル、アルキニルアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアリールアルキルおよび複素環式部分のそれぞれは、非置換であるか、もしくは同じであっても異なっていてもよい１つ以上の部分で必要に応じて置換され得、各部分は、Ｈ、ハロ、アルキル、トリフルオロメチル、−ＯＲ^８、−ＮＲ^８Ｒ^９、−ＳＲ^８、−ＳＯ_２Ｒ^９、−ＣＮ、−ＳＯ_２ＮＲ^８Ｒ^９、−ＣＦ_３および−ＮＯ_２からなる群より独立して選択され；
Ｒ^４は、Ｈ、ハロ、ハロアルキル、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、シクロアルキル、シクロアルキルアルキル、アルケニルアルキル、アルキニルアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアリールアルキル、−ＮＲ^８Ｒ^９、−ＮＲ^８ＣＯＲ^９、−ＮＲ^８ＳＯ_２Ｒ^９、−ＣＯＲ^８、−ＣＯ_２Ｒ^８、−ＣＯＮＲ^８Ｒ^９、−ＣＨ_２ＯＲ^８、−ＯＲ^８、−ＳＲ^８、−ＳＯ_２Ｒ^８、−Ｓ（Ｏ_２）ＮＲ^８Ｒ^９、−Ｓ（Ｏ_２）アリール、−Ｓ（Ｏ_２）ヘテロアリール、−Ｃ（Ｏ）ＯＲ^９、−Ｃ（Ｏ）アリール、−Ｃ（Ｏ）ヘテロアリール、−（ＣＨＲ^５）_ｎ−アリール、−（ＣＨＲ^５）_ｎ−ヘテロアリール、

Wherein alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, hetero, as indicated above for R ³ Each of the aryl, heteroarylalkyl and heterocyclic moieties may be unsubstituted or optionally substituted with one or more moieties, which may be the same or different, each moiety being H , Halo, alkyl, trifluoromethyl, —OR ⁸ , —NR ⁸ R ⁹ , —SR ⁸ , —SO ₂ R ⁹ , —CN, —SO ₂ NR ⁸ R ⁹ , —CF ₃ and —NO _2. Selected more independently;
R ⁴ is H, halo, haloalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,- ^{NR 8 R 9, -NR 8 COR} 9, -NR 8 SO 2 R 9, -COR 8, -CO 2 R 8, -CONR 8 R 9, -CH 2 OR 8, -OR 8, -SR 8, - _{^{SO 2 R 8, -S (O}} 2) NR 8 R 9, -S (O 2) aryl, -S _{(O 2)} ^{heteroaryl, -C (O) OR 9,} -C (O) aryl, -C (O) heteroaryl, - ^(CHR _{5) n} - aryl, - ^(CHR _{5) n} - heteroaryl,

からなる群より選択され、ここで、Ｒ^４に関して上に示したアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、シクロアルキル、シクロアルキルアルキル、アルケニルアルキル、アルキニルアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアリールアルキルおよび複素環式部分のそれぞれは、非置換であるか、もしくは同じであっても異なっていてもよい１つ以上の部分で必要に応じて置換され得、各部分は、Ｈ、ハロ、アルキル、トリフルオロメチル、−ＯＲ^８、−ＮＲ^８Ｒ^９、−ＳＲ^８、−ＳＯ_２Ｒ^９、−ＣＮ、−ＳＯ_２ＮＲ^８Ｒ^９、−ＣＦ_３および−ＮＯ_２；からなる群より独立して選択され；
Ｒ^ａは、Ｈ、ハロ、ハロアルキル、アルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、シクロアルキル、シクロアルキルアルキル、アルケニルアルキル、アルキニルアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアリールアルキル、−ＮＲ^８Ｒ^９、−ＮＲ^８ＣＯＲ^９、−ＮＲ^８ＳＯ_２Ｒ^９、−ＣＯＲ^８、−ＣＯ_２Ｒ^８、−ＣＯＮＲ^８Ｒ^９、−ＣＨ_２ＯＲ^８、−ＯＲ^８、−ＳＲ^８、−ＳＯ_２Ｒ^８、−Ｓ（Ｏ_２）ＮＲ^８Ｒ^９、−Ｓ（Ｏ_２）アリール、−Ｓ（Ｏ_２）ヘテロアリール、−Ｃ（Ｏ）ＯＲ^９、−Ｃ（Ｏ）アリール、−Ｃ（Ｏ）ヘテロアリール、−（ＣＨＲ^５）_ｎ−アリール、−（ＣＨＲ^５）_ｎ−ヘテロアリール、

Wherein alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, hetero, as indicated above for R ⁴ Each of the aryl, heteroarylalkyl and heterocyclic moieties may be unsubstituted or optionally substituted with one or more moieties, which may be the same or different, each moiety being H , Halo, alkyl, trifluoromethyl, —OR ⁸ , —NR ⁸ R ⁹ , —SR ⁸ , —SO ₂ R ⁹ , —CN, —SO ₂ NR ⁸ R ⁹ , —CF ₃ and —NO ₂ . Selected independently from the group;
R ^a is H, halo, haloalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,- ^{NR 8 R 9, -NR 8 COR} 9, -NR 8 SO 2 R 9, -COR 8, -CO 2 R 8, -CONR 8 R 9, -CH 2 OR 8, -OR 8, -SR 8, - _{^{SO 2 R 8, -S (O}} 2) NR 8 R 9, -S (O 2) aryl, -S _{(O 2)} ^{heteroaryl, -C (O) OR 9,} -C (O) aryl, -C (O) heteroaryl, - ^(CHR _{5) n} - aryl, - ^(CHR _{5) n} - heteroaryl,

からなる群より選択され、ここで、Ｒ^ａに関して上に示したアルキル、アルケニル、アルキニル、アリール、アリールアルキル、アリールアルケニル、シクロアルキル、シクロアルキルアルキル、アルケニルアルキル、アルキニルアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアリールアルキルおよび複素環式部分のそれぞれは、非置換であるか、もしくは同じであっても異なっていてもよい１つ以上の部分で必要に応じて置換され得、各部分は、Ｈ、ハロ、アルキル、トリフルオロメチル、−ＯＲ^８、−ＮＲ^８Ｒ^９、−ＳＲ^８、−ＳＯ_２Ｒ^９、−ＣＮ、−ＳＯ_２ＮＲ^８Ｒ^９、−ＣＦ_３および−ＮＯ_２；からなる群より独立して選択され；
Ｒ^５は、Ｈ、アルキル、アリールもしくはシクロアルキルからなる群より選択され、
Ｒ^６は、Ｈ、アルキル、アルケニル、アリール、アリールアルキル、アリールアルケニル、シクロアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群より選択され、ここで、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールおよびヘテロアリールアルキル基のそれぞれは、非置換であるか、もしくは同じであっても異なっていてもよい１つ以上の部分で必要に応じて置換され得、各部分は、ハロ、アルキル、アリール、シクロアルキル、ヘテロシクリルアルキル、−ＣＦ_３、−ＯＣＦ_３、−ＣＮ、−ＯＲ^５、−ＮＲ^５Ｒ^１０、−Ｃ（Ｒ^５Ｒ^１１）_ｐ−Ｒ^９、−Ｎ（Ｒ^５）Ｂｏｃ、−（ＣＲ^５Ｒ^１１）_ｐＯＲ^５、−Ｃ（Ｏ_２）Ｒ^５、−Ｃ（Ｏ）Ｒ^５、−Ｃ（Ｏ）ＮＲ^５Ｒ^１０、−ＳＯ_３Ｈ、−ＳＲ^１０、−Ｓ（Ｏ_２）Ｒ^７、−Ｓ（Ｏ_２）ＮＲ^５Ｒ^１０、−Ｎ（Ｒ^５）Ｓ（Ｏ_２）Ｒ^７、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｒ^７および−Ｎ（Ｒ^５）Ｃ（Ｏ）ＮＲ^５Ｒ^１０からなる群より独立して選択され；
Ｒ^７は、アルキル、シクロアルキル、アリール、アリールアルケニル、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロアリールアルケニルおよびヘテロシクリルからなる群より選択され、ここで、アルキル、シクロアルキル、ヘテロアリールアルキル、アリール、アリールアルケニル、ヘテロアリール、アリールアルキル、ヘテロアリールアルキル、ヘテロアリールアルケニルおよびヘテロシクリルのそれぞれは、非置換であるか、もしくは同じであっても異なっていてもよい１つ以上の部分で必要に応じて、独立して置換され得、各部分は、ハロ、アルキル、アリール、シクロアルキル、ＣＦ_３、ＯＣＦ_３、ＣＮ、−ＯＲ^５、−ＮＲ^５Ｒ^１０、−ＣＨ_２ＯＲ^５、−Ｃ（Ｏ_２）Ｒ^５、−Ｃ（Ｏ）ＮＲ^５Ｒ^１０、−Ｃ（Ｏ）Ｒ^５、−ＳＲ^１０、−Ｓ（Ｏ_２）Ｒ^１０、−Ｓ（Ｏ_２）ＮＲ^５Ｒ^１０、−Ｎ（Ｒ^５）Ｓ（Ｏ_２）Ｒ^１０、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｒ^１０および−Ｎ（Ｒ^５）Ｃ（Ｏ）ＮＲ^５Ｒ^１０からなる群より独立して選択され；
Ｒ^８は、Ｈ、−ＯＲ^６、−ＮＲ^５Ｒ^６、−Ｃ（Ｏ）ＮＲ^５Ｒ^１０、−Ｓ（Ｏ_２）ＮＲ^５Ｒ^１０、−Ｃ（Ｏ）Ｒ^７、−Ｃ（＝Ｎ−ＣＮ）−ＮＨ_２、−Ｃ（＝ＮＨ）−ＮＨＲ^５、ヘテロシクリル、−Ｓ（Ｏ_２）Ｒ^７、

Wherein alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, hetero, as indicated above for R ^a Each of the aryl, heteroarylalkyl and heterocyclic moieties may be unsubstituted or optionally substituted with one or more moieties, which may be the same or different, each moiety being H , Halo, alkyl, trifluoromethyl, —OR ⁸ , —NR ⁸ R ⁹ , —SR ⁸ , —SO ₂ R ⁹ , —CN, —SO ₂ NR ⁸ R ⁹ , —CF ₃ and —NO ₂ . Selected independently from the group;
R ⁵ is selected from the group consisting of H, alkyl, aryl or cycloalkyl;
R ⁶ is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein alkyl, alkenyl, aryl, arylalkyl Each of the, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups can be optionally substituted with one or more moieties that may be unsubstituted or the same or different. , each part, halo, alkyl, aryl, cycloalkyl, _{^{heterocyclylalkyl, -CF 3, -OCF 3, -CN}} , -OR 5, -NR 5 R 10, -C (R 5 R 11) p -R 9 , ^-N (R 5) Boc, _{^{(CR 5 R 11) p OR}} 5, -C (O 2) R 5, -C (O) R 5, -C (O) NR 5 R 10, -SO 3 H, -SR 10, -S (O _{^{2) R 7, -S (O}} 2) NR 5 R 10, -N (R 5) S (O 2) R 7, -N (R 5) C (O) R 7 and -N ^(R 5) C (O) independently selected from the group consisting of NR ⁵ R ¹⁰ ;
R ⁷ is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl, wherein alkyl, cycloalkyl, heteroarylalkyl, aryl, Each of arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl is optionally substituted with one or more moieties that may be unsubstituted or the same or different, independently may be substituted, each portion is halo, alkyl, aryl, _{^{cycloalkyl, CF 3, OCF 3, CN}} , -OR 5, -NR 5 R 10, -CH 2 OR 5, -C (O 2) ^{R 5, -C (O) NR} 5 _{^{10, -C (O) R 5}} , -SR 10, -S (O 2) R 10, -S (O 2) NR 5 R 10, -N (R 5) S (O 2) R 10, -N Independently selected from the group consisting of (R ⁵ ) C (O) R ¹⁰ and —N (R ⁵ ) C (O) NR ⁵ R ¹⁰ ;
R ⁸ is H, —OR ⁶ , —NR ⁵ R ⁶ , —C (O) NR ⁵ R ¹⁰ , —S (O ₂ ) NR ⁵ R ¹⁰ , —C (O) R ⁷ , —C (= N _{-CN) -NH 2, -C (=} NH) -NHR 5, ^{_{heterocyclyl, -S (O 2) R 7}} ,

−ＯＲ^１０、−ＣＦ_３、アルキル、アルケニル、アリール、アリールアルキル、アリールアルケニル、シクロアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群より選択され、ここで、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールおよびヘテロアリールアルキル基のそれぞれは、非置換であるか、もしくは同じであっても異なっていてもよい１つ以上の部分で必要に応じて置換され得、各部分は、ハロ、アルキル、アリール、シクロアルキル、ヘテロシクリルアルキル、−ＣＦ_３、−ＯＣＦ_３、−ＣＮ、−ＯＲ^５、−ＮＲ^５Ｒ^１０、−Ｃ（Ｒ^５Ｒ^１１）_ｐ−Ｒ^９、−Ｎ（Ｒ^５）Ｂｏｃ、−（ＣＲ^５Ｒ^１１）_ｐＯＲ^５、−Ｃ（Ｏ_２）Ｒ^５、−Ｃ（Ｏ）Ｒ^５、−Ｃ（Ｏ）ＮＲ^５Ｒ^１０、−ＳＯ_３Ｈ、−ＳＲ^１０、−Ｓ（Ｏ_２）Ｒ^７、−Ｓ（Ｏ_２）ＮＲ^５Ｒ^１０、−Ｎ（Ｒ^５）Ｓ（Ｏ_２）Ｒ^７、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｒ^７および−Ｎ（Ｒ^５）Ｃ（Ｏ）ＮＲ^５Ｒ^１０からなる群より独立して選択され；
Ｒ^８ａは、−ＯＲ^６、−ＮＲ^５Ｒ^６、−Ｃ（Ｏ）ＮＲ^５Ｒ^１０、−Ｓ（Ｏ_２）ＮＲ^５Ｒ^１０、−Ｃ（Ｏ）Ｒ^７、−Ｃ（＝Ｎ−ＣＮ）−ＮＨ_２、−Ｃ（＝ＮＨ）−ＮＨＲ^５、ヘテロシクリル、−Ｓ（Ｏ_２）Ｒ^７、

—OR ¹⁰ , —CF ₃ , alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein alkyl, alkenyl, aryl, Each of the arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups is unsubstituted or optionally substituted with one or more moieties that may be the same or different are obtained, each portion, halo, alkyl, aryl, cycloalkyl, _{^{heterocyclylalkyl, -CF 3, -OCF 3, -CN}} , -OR 5, -NR 5 R 10, -C (R 5 R 11) p - R ^9, -N (R _{^{) Boc, - (CR 5 R}} 11) p OR 5, -C (O 2) R 5, -C (O) R 5, -C (O) NR 5 R 10, -SO 3 H, -SR 10, _{^{-S (O 2) R 7,}} -S (O 2) NR 5 R 10, -N (R 5) S (O 2) R 7, -N (R 5) C (O) R 7 and -N ( R ⁵ ) independently selected from the group consisting of C (O) NR ⁵ R ¹⁰ ;
R ^{8a is, -OR 6, -NR 5 R 6} , -C (O) NR 5 R 10, -S (O 2) NR 5 R 10, -C (O) R 7, -C (= N-CN _{) -NH 2, -C (= NH} ) -NHR 5, ^{_{heterocyclyl, -S (O 2) R 7}} ,

、−ＯＲ^１０、−ＣＦ_３、アルキル、アルケニル、アリール、アリールアルキル、アリールアルケニル、シクロアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群より選択され、ここで、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールおよびヘテロアリールアルキル基のそれぞれは、非置換であるか、もしくは同じであっても異なっていてもよい１つ以上の部分で必要に応じて置換され得、各部分は、ハロ、アルキル、アリール、シクロアルキル、ヘテロシクリルアルキル、−ＣＦ_３、−ＯＣＦ_３、−ＣＮ、−ＯＲ^５、−ＮＲ^５Ｒ^１０、−Ｃ（Ｒ^５Ｒ^１１）_ｐ−Ｒ^９、−Ｎ（Ｒ^５）Ｂｏｃ、−（ＣＲ^５Ｒ^１１）_ｐＯＲ^５、−Ｃ（Ｏ_２）Ｒ^５、−Ｃ（Ｏ）Ｒ^５、−Ｃ（Ｏ）ＮＲ^５Ｒ^１０、−ＳＯ_３Ｈ、−ＳＲ^１０、−Ｓ（Ｏ_２）Ｒ^７、−Ｓ（Ｏ_２）ＮＲ^５Ｒ^１０、−Ｎ（Ｒ^５）Ｓ（Ｏ_２）Ｒ^７、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｒ^７および−Ｎ（Ｒ^５）Ｃ（Ｏ）ＮＲ^５Ｒ^１０からなる群より独立して選択され；
Ｒ^８ｂは、−ＯＲ^６、−ＮＲ^５Ｒ^６、−Ｃ（Ｏ）ＮＲ^５Ｒ^１０、−Ｓ（Ｏ_２）ＮＲ^５Ｒ^１０、−Ｃ（Ｏ）Ｒ^７、−Ｃ（＝Ｎ−ＣＮ）−ＮＨ_２、−Ｃ（＝ＮＨ）−ＮＨＲ^５、ヘテロシクリル、−Ｓ（Ｏ_２）Ｒ^７、

, —OR ¹⁰ , —CF ₃ , alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein alkyl, alkenyl, aryl Each of the, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups is optionally substituted with one or more moieties that may be unsubstituted or the same or different. Each moiety may be substituted, each halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, —CF ₃ , —OCF ₃ , —CN, —OR ⁵ , —NR ⁵ R ¹⁰ , —C (R ⁵ R ¹¹ ) _p -R ^9, -N (R _{^{5) Boc, - (CR 5}} R 11) p OR 5, -C (O 2) R 5, -C (O) R 5, -C (O) NR 5 R 10, -SO 3 H, -SR 10 _{^{, -S (O 2) R 7}} , -S (O 2) NR 5 R 10, -N (R 5) S (O 2) R 7, -N (R 5) C (O) R 7 and -N Independently selected from the group consisting of (R ⁵ ) C (O) NR ⁵ R ¹⁰ ;
R ^{8b is, -OR 6, -NR 5 R 6} , -C (O) NR 5 R 10, -S (O 2) NR 5 R 10, -C (O) R 7, -C (= N-CN _{) -NH 2, -C (= NH} ) -NHR 5, ^{_{heterocyclyl, -S (O 2) R 7}} ,

、−ＯＲ^１０、−ＣＦ_３、アルケニル、アリール、アリールアルキル、アリールアルケニル、シクロアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群より選択され、ここで、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールおよびヘテロアリールアルキル基のそれぞれは、非置換であるか、もしくは同じであっても異なっていてもよい１つ以上の部分で必要に応じて置換され得、各部分は、ハロ、アルキル、アリール、シクロアルキル、ヘテロシクリルアルキル、−ＣＦ_３、−ＯＣＦ_３、−ＣＮ、−ＯＲ^５、−ＮＲ^５Ｒ^１０、−Ｃ（Ｒ^５Ｒ^１１）_ｐ−Ｒ^９、−Ｎ（Ｒ^５）Ｂｏｃ、−（ＣＲ^５Ｒ^１１）_ｐＯＲ^５、−Ｃ（Ｏ_２）Ｒ^５、−Ｃ（Ｏ）Ｒ^５、−Ｃ（Ｏ）ＮＲ^５Ｒ^１０、−ＳＯ_３Ｈ、−ＳＲ^１０、−Ｓ（Ｏ_２）Ｒ^７、−Ｓ（Ｏ_２）ＮＲ^５Ｒ^１０、−Ｎ（Ｒ^５）Ｓ（Ｏ_２）Ｒ^７、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｒ^７および−Ｎ（Ｒ^５）Ｃ（Ｏ）ＮＲ^５Ｒ^１０からなる群より独立して選択され；
Ｒ^９は、Ｈ、−ＯＲ^６、−ＮＲ^５Ｒ^６、−Ｃ（Ｏ）ＮＲ^５Ｒ^１０、−Ｓ（Ｏ_２）ＮＲ^５Ｒ^１０、−Ｃ（Ｏ）Ｒ^７、−Ｃ（＝Ｎ−ＣＮ）−ＮＨ_２、−Ｃ（＝ＮＨ）−ＮＨＲ^５、ヘテロシクリル、−Ｓ（Ｏ_２）Ｒ^７、

, —OR ¹⁰ , —CF ₃ , alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein alkyl, alkenyl, aryl, aryl Each of the alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups is unsubstituted or optionally substituted with one or more moieties, which may be the same or different. the resulting, each portion, halo, alkyl, aryl, cycloalkyl, _{^{heterocyclylalkyl, -CF 3, -OCF 3, -CN}} , -OR 5, -NR 5 R 10, -C (R 5 R 11) p -R ^9, -N ^(R 5) Bo _{^{, - (CR 5 R 11)}} p OR 5, -C (O 2) R 5, -C (O) R 5, -C (O) NR 5 R 10, -SO 3 H, -SR 10, -S _{^{(O 2) R 7, -S}} (O 2) NR 5 R 10, -N (R 5) S (O 2) R 7, -N (R 5) C (O) R 7 and -N ^{(R 5} ) Independently selected from the group consisting of C (O) NR ⁵ R ¹⁰ ;
R ⁹ is H, —OR ⁶ , —NR ⁵ R ⁶ , —C (O) NR ⁵ R ¹⁰ , —S (O ₂ ) NR ⁵ R ¹⁰ , —C (O) R ⁷ , —C (= N _{-CN) -NH 2, -C (=} NH) -NHR 5, ^{_{heterocyclyl, -S (O 2) R 7}} ,

、−ＯＲ^１０、−ＣＦ_３、アルキル、アルケニル、アリール、アリールアルキル、アリールアルケニル、シクロアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群より選択され、ここで、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールおよびヘテロアリールアルキル基のそれぞれは、非置換であるか、もしくは同じであっても異なっていてもよい１つ以上の部分で必要に応じて置換され得、各部分は、ハロ、アルキル、アリール、シクロアルキル、ヘテロシクリルアルキル、−ＣＦ_３、−ＯＣＦ_３、−ＣＮ、−ＯＲ^５、−ＮＲ^５Ｒ^１０、−Ｃ（Ｒ^５Ｒ^１１）_ｐ−Ｒ^９、−Ｎ（Ｒ^５）Ｂｏｃ、−（ＣＲ^５Ｒ^１１）_ｐＯＲ^５、−Ｃ（Ｏ_２）Ｒ^５、−Ｃ（Ｏ）Ｒ^５、−Ｃ（Ｏ）ＮＲ^５Ｒ^１０、−ＳＯ_３Ｈ、−ＳＲ^１０、−Ｓ（Ｏ_２）Ｒ^７、−Ｓ（Ｏ_２）ＮＲ^５Ｒ^１０、−Ｎ（Ｒ^５）Ｓ（Ｏ_２）Ｒ^７、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｒ^７および−Ｎ（Ｒ^５）Ｃ（Ｏ）ＮＲ^５Ｒ^１０からなる群より独立して選択され；
Ｒ^１０は、Ｈ、アルキル、アルケニル、アリール、アリールアルキル、アリールアルケニル、シクロアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールおよびヘテロアリールアルキルからなる群より選択され、ここで、アルキル、アルケニル、アリール、アリールアルキル、シクロアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールおよびヘテロアリールアルキル基のそれぞれは、非置換であるか、もしくは同じであっても異なっていてもよい１つ以上の部分で必要に応じて置換され得、各部分は、ハロ、アルキル、アリール、シクロアルキル、ヘテロシクリルアルキル、−ＣＦ_３、−ＯＣＦ_３、−ＣＮ、−ＯＲ^５、−ＮＲ^５Ｒ^１１、−Ｃ（Ｒ^５Ｒ^１１）_ｐ−Ｒ^９、−Ｎ（Ｒ^５）Ｂｏｃ、−（ＣＲ^５Ｒ^１１）_ｐＯＲ^５、−Ｃ（Ｏ_２）Ｒ^５、−Ｃ（Ｏ）Ｒ^５、−Ｃ（Ｏ）ＮＲ^５Ｒ^１１、−ＳＯ_３Ｈ、−ＳＲ^１０、−Ｓ（Ｏ_２）Ｒ^７、−Ｓ（Ｏ_２）ＮＲ^５Ｒ^１１、−Ｎ（Ｒ^５）Ｓ（Ｏ_２）Ｒ^７、−Ｎ（Ｒ^５）Ｃ（Ｏ）Ｒ^７および−Ｎ（Ｒ^５）Ｃ（Ｏ）ＮＲ^５Ｒ^１１からなる群より独立して選択されるか；
あるいは必要に応じて（ｉ）部分−ＮＲ^５Ｒ^１１内のＲ^５およびＲ^１１か、もしくは（ｉｉ）部分−ＮＲ^５Ｒ^６内のＲ^５およびＲ^６が一緒に結合して、シクロアルキルもしくはヘテロシクリル部分を形成し得、シクロアルキルもしくはヘテロシクリル部分のそれぞれは、非置換であるか、もしくは１つ以上のＲ^９基で必要に応じて独立して置換され；
Ｒ^１１は、Ｈ、ハロもしくはアルキルであり；
ｍは、０〜４であり；
ｎは、１〜４であり；そして
ｐは、１〜４であり、
但し：
（ａ） Ｒ^２が上記のように定義される場合、Ｒ^３、Ｒ^４およびＲ^ａのうちの少なくとも１つが、−ＮＨ_２、−ＯＨ、アルコキシ、アルキルチオ、ハロ、アルキニル、アルケニルアルキルおよびアルキニルアルキルからなる群より選択されるか、または
（ｂ） Ｒ^３、Ｒ^４およびＲ^ａが上記のように定義される場合、Ｒ^２は、アルキル、シクロアルキル、シクロアルキルアルキル、ハロアルキル、アルケニル、アルキニル、アルケニルアルキル、アルキニルアルキル、トリフルオロメチル、−ＯＣＦ_３、−ＯＲ^８ａ、−ＳＲ^８および−ＮＲ^８ＣＯＮＲ^８Ｒ^９からなる群より選択されるという条件である。

, —OR ¹⁰ , —CF ₃ , alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein alkyl, alkenyl, aryl Each of the, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups is optionally substituted with one or more moieties that may be unsubstituted or the same or different. Each moiety may be substituted, each halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, —CF ₃ , —OCF ₃ , —CN, —OR ⁵ , —NR ⁵ R ¹⁰ , —C (R ⁵ R ¹¹ ) _p -R ^9, -N (R _{^{5) Boc, - (CR 5}} R 11) p OR 5, -C (O 2) R 5, -C (O) R 5, -C (O) NR 5 R 10, -SO 3 H, -SR 10 _{^{, -S (O 2) R 7}} , -S (O 2) NR 5 R 10, -N (R 5) S (O 2) R 7, -N (R 5) C (O) R 7 and -N Independently selected from the group consisting of (R ⁵ ) C (O) NR ⁵ R ¹⁰ ;
R ¹⁰ is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein alkyl, alkenyl, aryl, arylalkyl Each of the cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups can be optionally substituted with one or more moieties that may be unsubstituted or the same or different. , each part, halo, alkyl, aryl, cycloalkyl, _{^{heterocyclylalkyl, -CF 3, -OCF 3, -CN}} , -OR 5, -NR 5 R 11, -C (R 5 R 11) p -R 9 , ^-N (R 5) Boc _{^{- (CR 5 R 11) p}} OR 5, -C (O 2) R 5, -C (O) R 5, -C (O) NR 5 R 11, -SO 3 H, -SR 10, -S ( _{^{O 2) R 7, -S (}} O 2) NR 5 R 11, -N (R 5) S (O 2) R 7, -N (R 5) C (O) R 7 and -N ^(R 5) Is independently selected from the group consisting of C (O) NR ⁵ R ¹¹ ;
Or optionally (i) partial ^-NR 5 or ^{R 5} and ^{R 11} in ^{R 11,} or (ii) moiety ^-NR 5 ^{R 5} and ^{R 6} in ^{R 6} are bonded together, cycloalkyl or A heterocyclyl moiety may be formed, each cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently substituted with one or more R ⁹ groups;
R ¹¹ is H, halo or alkyl;
m is 0-4;
n is 1-4; and p is 1-4.
However:
(A) When R ² is defined as above, at least one of R ³ , R ⁴ and R ^a is —NH ₂ , —OH, alkoxy, alkylthio, halo, alkynyl, alkenylalkyl and alkynylalkyl. Or (b) when R ³ , R ⁴ and R ^a are defined as above, R ² is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkenyl, alkynyl, It is a condition that it is selected from the group consisting of alkenylalkyl, alkynylalkyl, trifluoromethyl, —OCF ₃ , —OR ^8a , —SR ⁸ and —NR ⁸ CONR ⁸ R ⁹ .

  The compounds of formula I may be useful as protein kinase inhibitors and are proliferative diseases (eg cancer), inflammation and arthritis, neurodegenerative diseases (eg Alzheimer's disease), cardiovascular diseases, viral diseases and fungal It can be useful in the treatment and prevention of disease.

(Detailed explanation)
The present invention provides substituted pyrazolo [1,5-a] pyrimidine compounds represented by Structural Formula (I), or pharmaceutically acceptable salts, solvates, esters or prodrugs thereof, wherein The part is as described above.

Referring to formula (I) above, in some embodiments, R ² is H.

In other embodiments, R ² is Br.

In other embodiments, R ² is selected from the group consisting of Cl, —SH, —CN, alkyl, alkenyl, alkynyl, and cyclopropyl.

In other embodiments, R ² is cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, —OCF ₃ , —CO ₂ R ⁸ , —CONR ⁸ R ⁹ , —OR ^8a , —SR ⁸ , —SO _{2. ^{R 8, -SO 2 NR 8 R}} 9, -NR 8 SO 2 R 9, is selected from the group consisting of -NR 8 COR ⁹ and ^{-NR 8} CONR 8 R ^9.

In some embodiments, R ³ is benzyl.

In other embodiments, R ³ is methyl.

In other embodiments, R ³ is aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —S (O ₂ ) aryl, —S (O _2). ) heteroaryl, -C (O) aryl, -C (O) heteroaryl, - ^(CHR _{5) n} - aryl, - ^(CHR _{5) n} - heteroaryl,

からなる群より選択され、ここで、Ｒ^３に関して上に示したアリール、アリールアルキル、アリールアルケニル、シクロアルキル、シクロアルキルアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアリールアルキルおよび複素環部分は、非置換であるか、もしくは同じであっても異なっていてもよい１つ以上の部分で必要に応じて置換され得、各部分は、Ｈ、ハロ、アルキル、トリフルオロメチル、−ＯＲ^８、−ＮＲ^８Ｒ^９、−ＳＲ^８、−ＳＯ_２Ｒ^９、−ＣＮ、−ＳＯ_２ＮＲ^８Ｒ^９、−ＣＦ_３および−ＮＯ_２からなる群より独立して選択される。

Wherein the aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and heterocyclic moieties shown above for R ³ are non- It may be substituted or optionally substituted with one or more moieties, which may be the same or different, each moiety being H, halo, alkyl, trifluoromethyl, —OR ⁸ , —NR ⁸ R ⁹ , —SR ⁸ , —SO ₂ R ⁹ , —CN, —SO ₂ NR ⁸ R ⁹ , —CF ₃ and —NO ₂ are independently selected.

In other embodiments, R ³ is haloalkyl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, —NR ⁵ R ^8a , —NR ⁸ COR ⁹ , —NR ⁸ SO ₂ R ⁹ , —COR ⁸ , —CO ₂ R ⁸ , —CONR ⁸ R ⁹ , —CH ₂ OR ⁸ , —OR ^8b , —SR ⁸ , —SO ₂ R ⁸ , —S (O ₂ ) NR ⁸ R ⁹ , wherein alkyl, Alkenyl, alkynyl, alkenylalkyl, alkynylalkyl may be unsubstituted or optionally substituted with one or more moieties, which may be the same or different, each moiety being H, halo, Alkyl, trifluoromethyl, —OR ⁸ , —NR ⁸ R ⁹ , —SR ⁸ , —SO ₂ R ⁹ , —CN, —SO ₂ NR ⁸ R ⁹ , —CF ₃ and — Selected independently from the group consisting of NO ₂ .

In other embodiments, R ³ is alkoxy.

In other embodiments, R ³ is alkylthio.

In other embodiments, R ³ is

からなる群より選択される。

Selected from the group consisting of

In other embodiments, R ³ can be the same or different and each is 1 to 3 independently selected from the group consisting of phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups An aryl substituted with an aryl or heteroaryl group.

In other embodiments, R ³ may be the same or different and each is 1 to 3 independently selected from the group consisting of phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups Heteroaryl substituted with an aryl or heteroaryl group.

In other embodiments, R ³ is selected from the group consisting of heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl.

In some embodiments, R ³ is phenyl.

In some embodiments, R ⁴ is H.

In other embodiments, R ⁴ is selected from the group consisting of Cl, Br, —OH, —SH, alkyl, alkenyl, alkynyl, haloalkyl, and cyclopropyl.

In other embodiments, R ⁴ is —NH ₂ .

In other embodiments, R ⁴ is —OH.

In other embodiments, R ⁴ is alkoxy.
In other embodiments, R ⁴ is alkylthio.

In other embodiments, R ⁴ is halo.

In some embodiments, R ^a is —NH ₂ .

In other embodiments, R ^a is —OH.

In other embodiments, R ^a is alkoxy.

In other embodiments, R ^a is alkylthio.

In other embodiments, R ^a is halo.

In other embodiments, R ^a is Cl.

In some embodiments, R ⁵ is H.

  In some embodiments, n is 1.

  In some embodiments, p is 1.

  In another embodiment, the present invention provides compounds of the formula:

の化合物を提供し、ここで：Ｒ^２＝Ｒ^４＝Ｈであり；
Ｒ^３はアリールであり；そして
Ｒ^ａはアミンである。

Wherein R ² = R ⁴ = H;
R ³ is aryl; and R ^a is an amine.

  In another embodiment, the present invention provides compounds of the formula:

の化合物を提供し、ここで：Ｒ^２＝Ｒ^４＝Ｈであり；
Ｒ^３はフェニルであり；そして
Ｒ^ａはアミンである。

Wherein R ² = R ⁴ = H;
R ³ is phenyl; and R ^a is an amine.

  In another embodiment, the present invention provides compounds of the formula:

の化合物を提供し、ここで：Ｒ^２＝Ｒ^４＝Ｈであり；
Ｒ^３はアリールであり；そして
Ｒ^ａは−ＮＨ_２である。

Wherein R ² = R ⁴ = H;
R ³ is aryl; and R ^a is —NH ₂ .

  In another embodiment, the present invention provides compounds of the formula:

の化合物を提供し、ここで：Ｒ^２はハロであり；
Ｒ^３はアリールであり；
Ｒ^４はＨであり；そして
Ｒ^ａはアミンである。

Wherein R ² is halo;
R ³ is aryl;
R ⁴ is H; and R ^a is an amine.

  In another embodiment, the present invention provides compounds of the formula:

の化合物を提供し、ここで：Ｒ^２はブロモであり；
Ｒ^３はアリールであり；
Ｒ^４はＨであり；そして
Ｒ^ａはアミンである。

Wherein R ² is bromo;
R ³ is aryl;
R ⁴ is H; and R ^a is an amine.

  In another embodiment, the present invention provides compounds of the formula:

の化合物を提供し、ここで：Ｒ^２はブロモであり；
Ｒ^３はフェニルであり；
Ｒ^４はＨであり；そして
Ｒ^ａはアミンである。

Wherein R ² is bromo;
R ³ is phenyl;
R ⁴ is H; and R ^a is an amine.

  In another embodiment, the present invention provides compounds of the formula:

の化合物を提供し、ここで：Ｒ^２はブロモであり；
Ｒ^３はフェニルであり；
Ｒ^４はＨであり；そして
Ｒ^ａは−ＮＨ_２である。
別の実施形態において、本発明は、式：

Wherein R ² is bromo;
R ³ is phenyl;
R ⁴ is H; and R ^a is —NH ₂ .
In another embodiment, the present invention provides compounds of the formula:

の化合物を提供し、ここで：Ｒ^２＝Ｒ^４＝Ｈであり；
Ｒ^３はアリールであり；そして
Ｒ^ａは−ＯＨである。

Wherein R ² = R ⁴ = H;
R ³ is aryl; and R ^a is —OH.

  In another embodiment, the present invention provides compounds of the formula:

の化合物を提供し、ここで：Ｒ^２＝Ｒ^４＝Ｈであり；
Ｒ^３はフェニルであり；そして
Ｒ^ａは−ＯＨである。

Wherein R ² = R ⁴ = H;
R ³ is phenyl; and R ^a is —OH.

  Non-limiting examples of compounds of formula (I) include

が挙げられる。

Is mentioned.

As used above and throughout this disclosure, the following terms are to be understood to have the following meanings unless otherwise indicated:
“Patient” includes both human and animals.

  “Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups (eg methyl, ethyl or propyl) are attached to a linear alkyl chain. “Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. “Alkyl” may be unsubstituted or optionally substituted with one or more substituents, which may be the same or different, Is halo, alkyl, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH (alkyl), —NH (cycloalkyl), —N (alkyl) ₂ , carboxy and —C (O) O— Independently selected from the group consisting of alkyl. Non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.

  “Alkenyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, in which the chain may be straight or branched and the group may have about Contains 2 to about 15 carbon atoms. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups (eg methyl, ethyl or propyl) are attached to a linear alkenyl chain. “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain, which may be straight or branched. “Alkenyl” may be unsubstituted or optionally substituted with one or more substituents, which may be the same or different, and each substituent Are independently selected from the group consisting of halo, alkyl, aryl, cycloalkyl, cyano, alkoxy and -S (alkyl). Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

  “Alkylene” means a difunctional group obtained by removing a hydrogen atom from an alkyl group as defined above. Non-limiting examples of alkylene include methylene, ethylene and propylene.

  “Alkynyl” means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, wherein the chain can be straight or branched and the group can be about 2 to about Contains 15 carbon atoms in the chain. Preferred alkynyl groups contain about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups (eg methyl, ethyl or propyl) are attached to a linear alkynyl chain. “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain, which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. “Alkynyl” can be unsubstituted or optionally substituted with one or more substituents, which substituents can be the same or different, Are independently selected from the group consisting of alkyl, aryl and cycloalkyl.

  “Aryl” means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group may be optionally substituted with one or more “ring system substituents” which may be the same or different and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.

  “Heteroaryl” means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, wherein , One or more of the ring atoms is an element (one or a combination) different from carbon, for example, nitrogen, oxygen or sulfur. Preferred heteroaryls contain about 5 to about 6 ring atoms. “Heteroaryl” may be optionally substituted by one or more “ring system substituents” which may be the same or different and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The nitrogen atom of the heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridone), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo [1,2-a] pyridinyl, imidazo [2,1-b] thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzo Thienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1,2,4-to Azinyl, benzothiazolyl and the like. The term “heteroaryl” also refers to partially saturated heteroaryl moieties (eg, tetrahydroisoquinolyl, tetrahydroquinolyl, etc.).

  “Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl and alkyl are as previously described. Preferred aralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.

  “Alkylaryl” means an alkyl-aryl group in which alkyl and aryl are as previously described. Preferred alkylaryls contain a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.

  “Cycloalkyl” means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. Cycloalkyls may be optionally substituted with one or more “ring system substituents” which may be the same or different and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.

  “Cycloalkylalkyl” means a cycloalkyl moiety as defined above attached via an alkyl moiety (defined above) to a parent nucleus. Non-limiting examples of suitable cycloalkylalkyl include cyclohexylmethyl, adamantylmethyl and the like.

  “Cycloalkenyl” is a non-aromatic monocyclic containing at least one carbon-carbon double bond containing about 3 to about 10 carbon atoms (preferably about 5 to about 10 carbon atoms). Or a polycyclic ring system. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. A cycloalkenyl may be optionally substituted with one or more “ring system substituents” which may be the same or different and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cyclohepta-1,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.

  “Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above attached via an alkyl moiety (defined above) to a parent nucleus. Non-limiting examples of suitable cycloalkenylalkyl include cyclopentenylmethyl, cyclohexenylmethyl and the like.

  “Halogen” means fluorine, chlorine, bromine or iodine. Preference is given to fluorine, chlorine and bromine.

“Ring system substituent” means a substituent attached to an aromatic or non-aromatic ring system (eg, in lieu of available hydrogen on the ring system). The ring system substituents may be the same or different and each substituent may be alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, Hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, _{heterocyclyl, -C (= N-CN)} -NH 2, -C (= NH) - _{H 2, -C (= NH)} -NH ( _{alkyl), Y 1 Y 2 N-,} Y 1 Y 2 N- alkyl _{-, Y 1 Y 2 NC (} O) -, Y 1 Y 2 NSO 2 - and - Independently selected from the group consisting of SO ₂ NY ₁ Y ₂ , wherein Y ₁ and Y ₂ may be the same or different and from the group consisting of hydrogen, alkyl, aryl, cycloalkyl and aralkyl. Independently selected. "Ring system substituent" can also mean a single moiety that simultaneously replaces two available hydrogens on one adjacent carbon atom on the ring system (one H on each carbon). Examples of such moieties include methylenedioxy, ethylenedioxy, —C (CH ₃ ) ₂ — and the like, for example:

のような部分を形成する。

A part like this is formed.

  “Heteroarylalkyl” means a heteroaryl moiety as defined above attached via an alkyl moiety (defined above) to a parent nucleus. Non-limiting examples of suitable heteroaryl include 2-pyridinylmethyl, quinolinylmethyl and the like.

“Heterocyclyl” means a non-aromatic saturated monocyclic or polycyclic ring system containing about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, wherein Wherein one or more atoms in the ring system is an element different from carbon, for example, any one of nitrogen, oxygen, or sulfur, or a combination thereof. There are no adjacent oxygen and / or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in the heterocyclyl ring may be present protected as, for example, a -N (Boc), -N (CBz), -N (Tos) group; such protection is also part of this invention. It is considered to be. A heterocyclyl may be optionally substituted by one or more “ring system substituents” which may be the same or different and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
“Heterocyclyl” can also mean a single moiety (eg, carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Examples of such parts are pyrrolidone:

である。

It is.

  “Heterocyclylalkyl” means a heterocyclyl moiety as defined above attached via an alkyl moiety (defined above) to a parent nucleus. Non-limiting examples of suitable heterocyclylalkyl include piperidinylmethyl, piperazinylmethyl and the like.

  “Heterocyclenyl” is a non-aromatic mono- or polycyclic ring system comprising about 3 to about 10 ring atoms (preferably about 5 to about 10 ring atoms), wherein , One or more of the atoms in the ring system is an element (one or a combination) different from carbon (eg, a nitrogen, oxygen, or sulfur atom) and at least one carbon-carbon double bond Or the thing which has a carbon-nitrogen double bond is meant. There are no adjacent oxygen and / or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. A heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein “ring system substituent” is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S, S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3, 6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl , 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo [2.2.1] heptenyl, dihydrothiophenyl, dihydrothiopyranyl and the like. “Heterocyclenyl” may also mean a single moiety (eg, carbonyl), which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Examples of such moieties are pyrrolidinone:

である。

It is.

  “Heterocyclenylalkyl” means a heterocyclenyl moiety as defined above attached via an alkyl moiety (defined above) to a parent nucleus.

  In the heteroatom-containing ring system of the present invention, there is no hydroxyl group on the carbon atom adjacent to N, O or S, and no N or S group on the carbon adjacent to another heteroatom. You should be careful. So, for example, the ring:

内では、２および５で印をつけた炭素に直接結合した−ＯＨは存在しない。

Within, there is no —OH attached directly to the carbons marked 2 and 5.

  For example, the part:

のような互変異性の形態は、本発明の特定の実施形態において等価であるとみなされることにも注意するべきである。

It should also be noted that tautomeric forms such as are considered equivalent in certain embodiments of the invention.

  “Alkynylalkyl” means an alkynyl-alkyl-group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl group and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting example of a suitable alkynylalkyl group is propargylmethyl.

  “Heteroaralkyl” means a heteroaryl-alkyl-group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.

  “Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as defined above. Preferred hydroxyalkyl include lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

  “Acyl” means an HC (O) —, alkyl-C (O) — or cycloalkyl-C (O) — group in which the various groups are as described above. The bond to the parent moiety is through the carbonyl. Preferred acyls include lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.

  “Aroyl” means an aryl-C (O) — group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1-naphthoyl.

  “Alkoxy” means an alkyl-O— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, and n-butoxy. The bond to the parent moiety is through the ether oxygen.

  “Aryloxy” means an aryl-O— group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.

  “Aralkyloxy” means an aralkyl-O— group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1-naphthalenemethoxy or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen.

  “Alkylthio” means an alkyl-S— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through sulfur.

  “Arylthio” means an aryl-S— group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through sulfur.

  “Aralkylthio” means an aralkyl-S— group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through sulfur.

  “Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

  “Aryloxycarbonyl” means an aryl-O—C (O) — group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl.

  “Aralkoxycarbonyl” means an aralkyl-O—C (O) — group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S (O ₂ ) — group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.

“Arylsulfonyl” means an aryl-S (O ₂ ) — group. The bond to the parent moiety is through the sulfonyl.

  The term “substituted” means that one or more hydrogens of the indicated moiety is replaced with one selected from the group described, provided that the existing atom of the indicated atom is present. The condition is that the normal valence is not exceeded and this substitution results in a stable compound. Combinations with substituents and / or variables are permissible so long as such combinations result in stable compounds. By “stable compound” or “stable structure” is meant a compound that is sufficiently robust to withstand isolation to a useful degree of purity and formulation into an effective therapeutic agent.

  The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.

  The term “purified”, “purified form” or “isolated and purified form” for a compound refers to the compound after being isolated from a synthetic process or natural source or combination thereof. The physical state. Thus, the term “purified”, “purified form” or “isolated and purified form” for a compound is described herein or from purification processes well known to those skilled in the art. Refers to the physical state of the compound after it has been obtained in sufficient purity to be characterized by standard analytical techniques described herein or well known to those skilled in the art.

  It is also contemplated that any carbon and heteroatoms that do not meet the valences in the text, schemes, examples and tables herein are considered to have a sufficient number of hydrogen atoms to meet the valences. It should be noted.

  When a functional group in a compound is referred to as “protected”, this means that when this compound is subjected to a reaction, this group is modified to prevent undesired side reactions at protected positions. It means that. Suitable protecting groups are recognized by those skilled in the art, as well as by reference to standard textbooks (eg, TW Greene et al., Protective Groups in organic Synthesis (1991), Wiley, New York).

When any more than one variable (eg aryl, heterocycle, R ^2, etc.) is present in any constituent or in Formula I, its definition at each occurrence is defined as all other occurrences It is independent of its definition in the place.

  As used herein, the term “composition” results directly or indirectly from a product containing a particular component in a particular amount, as well as a combination of a particular component in a particular amount. It is intended to encompass any product.

  Prodrugs and solvates of the compounds of the invention are also contemplated herein. The discussion on prodrugs C. S. Symposium Series T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 and Bioreversible Carriers in Drug Design, (1987) Edward B. Roche (eds.), American Pharmaceutical Association and Pergamon Press. The term “prodrug” refers to a compound (eg, a drug precursor) that is transformed in vivo to yield a compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. means. This conversion can occur by various mechanisms (eg, by metabolic or chemical processes (eg, through hydrolysis in blood)). For a discussion of the use of prodrugs, see A. C. S. Symposium Series Vol. 14 T.W. Higuchi and W.H. By Stella, “Pro-drugs as Novel Delivery Systems” and by Bioreversible Carriers in Drug Design (ed.) Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

For example, if the compound of formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound has a carboxylic acid functional group, the prodrug may be a group containing a hydrogen atom of the acid group. (Eg (C ₁ -C ₈ ) alkyl, (C ₂ -C ₁₂ ) alkanoyloxymethyl, 1- (alkanoyloxy) ethyl having 4 to 9 carbon atoms, 1 having 5 to 10 carbon atoms -Methyl-1- (alkanoyloxy) -ethyl, alkoxycarbonyloxymethyl having 3-6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl having 4-7 carbon atoms, 5-8 carbons 1-methyl-1- (alkoxycarbonyloxy) ethyl having atoms, N- (alkoxycarbonyl) aminomethyl having 3 to 9 carbon atoms, 4 to 10 carbons 1- (N- (alkoxycarbonyl) amino) ethyl having atoms, 3-phthalidyl, 4-crotonolactonyl, .gamma.-butyrolactone-4-yl, di _{-N, N- (C 1 -C 2} ) alkylamino (C ₂ -C ₃ ) alkyl (eg β-dimethylaminoethyl), carbamoyl- (C ₁ -C ₂ ) alkyl, N, N-di (C ₁ -C ₂ ) alkylcarbamoyl- (C ₁ -C ₂ ) alkyl and piperidino _(C 2 -C ₃₎ alkyl may include esters formed by substituting pyrrolidino _(C 2 -C ₃₎ alkyl or morpholino _(C 2 -C ₃₎ alkyl, etc.).

Similarly, when the compound of formula (I) contains an alcohol functional group, the prodrug may be substituted with a hydrogen atom of the alcohol group (eg (C ₁ -C ₆ ) alkanoyloxymethyl, 1-((C ₁ -C ₆₎ alkanoyloxy) ethyl, 1-methyl _{-1 - ((C 1 -C 6} ) alkanoyloxy) _{ethyl, (C} 1 -C ₆₎ alkoxycarbonyloxymethyl, _N-(C 1 -C ₆₎ alkoxy Carbonylaminomethyl, succinoyl, (C ₁ -C ₆ ) alkanoyl, α-amino (C ₁ -C ₄ ) alkanyl, arylacyl and α-aminoacyl or α-aminoacyl-α-aminoacyl (where each α-aminoacyl group is independently selected from the naturally occurring L- amino _{acids), P (O) (OH} ) 2, -P (O) (O (C 1 -C 6) alkyl ) It may be formed by replacing ₂ or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), etc.).

When the compound of formula (I) contains an amine functional group, the prodrug may be substituted with a hydrogen atom in the amine group (eg, R and R ′ are each independently (C ₁ -C ₁₀ ) alkyl, (C _3- C ₇ ) cycloalkyl, benzyl, or R-carbonyl is natural α-aminoacyl or natural α-aminoacyl, R-carbonyl, RO-carbonyl, NRR′-carbonyl, Y ¹ is H, (C ₁ -C ₆₎ -C alkyl or benzyl ^{(OH) C (O) OY} 1, Y 2 is _(C 1 -C ₄₎ alkyl, ^{Y 3} is _(C 1 -C ₆₎ alkyl, carboxy ( C ₁ -C ₆₎ alkyl, amino _(C 1 -C ₄₎ alkyl or mono -N- or di -N, _N-(C 1 -C ₆₎ ^-C alkylaminoalkyl (OY ^{2) Y} 3, ⁴ is H or methyl and ^{Y 5} is mono -N- or di _{-N, N- (C 1 -C 6} ) alkylamino morpholino, -C piperidin-1-yl or pyrrolidin-1-yl ( Y ⁴ ) Y ⁵ etc.).

One or more compounds of the present invention may exist in the form of unsolvates and solvates with pharmaceutically acceptable solvents (eg, water, ethanol, etc.). It is intended to encompass both forms of solvate. “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves covalent bonds including varying degrees of ionic and hydrogen bonding. In certain instances, solvates can be isolated, for example, when one or more solvent molecules are incorporated into a crystalline solid crystal lattice. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolate, methanolate and the like. “Hydrate” is a solvate wherein the solvent molecule is H ₂ O.

  One or more compounds of the invention can be converted to a solvate if desired. The preparation of solvates is generally known. For example, M.M. Caira et al. Pharmaceutical Sci. 93 (3), 601-611 (2004) describe the preparation of antifungal fluconazole solvates in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvates, hydrates, etc. are described in E.C. C. van Tonder et al., AAPS PharmSciTech. 5 (1), article 12 (2004); L. Bingham et al., Chem. Commun. 603-604 (2001). A typical non-limiting process involves dissolving the compound of the present invention in the desired amount of the desired solvent (organic solvent or water or mixtures thereof) at a temperature above ambient and forming this solution into crystals. Cooling at a sufficient rate, the crystals are then isolated by standard methods. Analytical techniques (eg, IR spectroscopy) indicate the presence of the solvent (or water) in the crystal as a solvate (or hydrate).

  “Effective amount” or “therapeutically effective amount” is a compound or composition of the invention effective to inhibit the above-described diseases, thereby producing the desired therapeutic, ameliorative, inhibitory or prophylactic effect. It is meant to explain the amount of.

  The compounds of formula I can form salts, which are also within the scope of the invention. Unless indicated otherwise, references herein to a compound of formula I are understood to include a reference to a salt thereof. The term “salt” as used herein refers to acidic salts formed using inorganic and / or organic acids, and basic salts formed using inorganic and / or organic bases. Show. Furthermore, when a compound of Formula I contains both a basic moiety (eg, but not limited to pyridine or imidazole) and an acidic moiety (eg, but not limited to a carboxylic acid), a zwitterion (“molecule” Inner salt ") may be formed, and as used herein is included in the term" salt ". Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, but other salts are also useful. For example, by reacting a compound of Formula I with an amount (eg, an equal amount) of acid or base in a medium (eg, in a medium that precipitates a salt or in an aqueous medium that is then lyophilized). Salts of the compounds can be formed.

  Typical acid addition salts include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, fumarate Acid salt, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate, naphthalenesulfonate, nitrate, oxalate, phosphate, propionate, salicylic acid And salts, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as tosylate), and the like. In addition, acids that are generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are, for example, P.I. Stahl et al., Camille G. et al. (Edition) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; Berge et al., Journal of Pharmaceutical Sciences (1977) 66 (1) 1-19; Gould, International J. et al. of Pharmaceuticals (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York, and The Orange Book (Doo. Is being discussed in. These disclosures are incorporated herein by reference.

  Typical basic salts include ammonium salts, alkali metal salts (eg, sodium, lithium and potassium salts), alkaline earth metal salts (eg, calcium and magnesium salts), organic bases (eg, organic amines). ) (For example, dicyclohexylamine, t-butylamine), and a salt with an amino acid (for example, arginine, lysine). Basic nitrogen-containing groups include drugs (eg, lower alkyl halides (eg, methyl, ethyl and butyl chloride, bromide, and iodide), dialkyl sulfates (eg, dimethyl sulfate, diethyl sulfate, and dibutyl sulfate), It can be quaternized with long chain halides such as decyl, lauryl and stearyl chlorides, bromides, and iodides, aralkyl halides such as benzyl and phenethyl bromides, and the like.

  All such acidic and basic salts are intended to be pharmaceutically acceptable salts within the scope of the present invention, and all acidic and basic salts are intended for the purposes of the present invention. Is considered equivalent to the free form of the corresponding compound.

Pharmaceutically acceptable esters of the compounds of the present invention include the following groups: (1) Carboxylic acid esters obtained by esterification of hydroxy groups (where the non-carbonyl moiety of the carboxylic acid moiety of the ester group is Linear or branched alkyl (eg acetyl, n-propyl, t-butyl or n-butyl), alkoxyalkyl (eg methoxymethyl), aralkyl (eg benzyl), aryloxyalkyl (eg phenoxy) Methyl), aryl (eg, phenyl optionally substituted (eg, with halogen, C _1-4 alkyl or C _1-4 alkoxy or amino)); (2) sulfonate esters (eg, alkyl Sulfonyl or aralkylsulfonyl (eg, methanesulfuryl) Yl)); (3) amino acid esters (e.g., L- valyl or L- isoleucyl);. (4) phosphonate esters and (5) mono-, - di - or triphosphate phosphate esters, eg, _{C 1} It can be further esterified with _-20 alcohols or reactive derivatives thereof, or with 2,3-di (C _6-24 ) acylglycerols.

  Compounds of formula I, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.

  The compounds of formula (I) may contain asymmetric or chiral centers and therefore may exist in various stereoisomeric forms. All stereoisomeric forms of the compounds of formula (I), including racemic mixtures, and mixtures thereof are intended to be part of this invention. Furthermore, the present invention encompasses all geometric and positional isomers. For example, where a compound of formula (I) contains a double bond or fused ring, both cis- and trans-forms and mixtures thereof are included within the scope of the invention.

  Diastereomeric mixtures are separated into their individual diastereomers on the basis of their physical and chemical differences by methods well known to those skilled in the art (eg, by chromatography and / or fractional crystallization). obtain. Enantiomers can be converted to diastereomeric mixtures by reaction with a suitable optically active compound (eg, chiral auxiliary such as a chiral alcohol or Mosher acid chloride) and the diastereomers are separated. Can be separated by converting (eg, hydrolyzing) each diastereomer to the corresponding pure enantiomer. Also, some of the compounds of formula (I) may be atropisomers (eg, substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.

  It is also possible that the compounds of formula (I) may exist in different tautomeric forms, all such forms being within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included within the invention.

  All stereoisomers (eg, geometric isomers, optical isomers, etc.) of this compound (including salts, solvates, esters and prodrugs of this compound, and salts, solvates and esters of this prodrug) ) (For example, enantiomeric forms (which may exist even without an asymmetric carbon), rotational isomer forms, atropisomers, and diastereomeric forms due to asymmetric carbons on various substituents. Are obtained within the scope of the present invention, as are positional isomers (eg, 4-pyridyl and 3-pyridyl). (For example, where a compound of formula (I) contains a double bond or fused ring, both the cis- and trans-forms and mixtures thereof are encompassed within the scope of the invention. All keto-enol and imine-enamine forms of the present invention are encompassed within the present invention). Individual stereoisomers of the compounds of the invention may be substantially free of other isomers, for example, or may be, for example, as racemates, or with all other isomers, or other selected isomers. May be mixed with the body. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of terms such as “salts”, “solvates”, “esters”, “prodrugs”, enantiomers, stereoisomers, rotational isomers, tautomers, regioisomers, racemates of the compounds of the invention. It is intended to apply equally to salts, solvates, esters and prodrugs of the body or prodrug.

The present invention also includes isotopically-labeled compounds of the present invention in which one or more atoms are replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Except as otherwise noted, it is identical to the compounds detailed herein. Examples of isotopes that may be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine isotopes (eg, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, and ³⁶ Cl).

Certain isotopically-labelled compounds of formula (I) (eg, those labeled with ³ H and ¹⁴ C) are useful in compound and / or substrate tissue distribution assays. Tritium (ie, ³ H) and carbon-14 (ie, ¹⁴ C) isotopes are particularly preferred for their ease of preparation and ease of detection. In addition, substituents with heavier isotopes such as deuterium (ie, ² H) may have certain therapeutic benefits resulting from higher metabolic stability (eg, increased in vivo half-life or required dosage) May be preferable in some situations. Isotopically-labelled compounds of formula (I) are generally prepared using non-isotopically labeled reagents according to procedures similar to those disclosed in the schemes and / or examples herein below. It can be prepared by substituting with an appropriately isotopically labeled reagent.

  Polymorphic forms of the compounds of formula I and polymorphic forms of the salts, solvates, esters and prodrugs of the compounds of formula I are intended to be included in the present invention.

  The compounds of the invention may have pharmaceutical properties; in particular, the compounds of formula (I) may be protein kinase inhibitors, modulators or modulators. Non-limiting examples of protein kinases that can be inhibited, regulated or modulated include cyclin dependent kinases (CDK) (eg, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7 and CDK8), mitogens Activated protein kinase (MAPK / ERK), glycogen synthase kinase 3 (GSK3β), Chk kinase (eg, Chk1 and Chk2), Pim-1 kinase, tyrosine kinase (eg, HER subfamily (eg, EGFR (HER1), HER2) , HER3 and HER4)), insulin subfamily (eg including INS-R, IGF-IR, IR and IR-R), PDGF subfamily (eg PDGF-α and β Including Scepter, CSFIR, c-kit and FLK-II), FLK family (eg, kinase insert domain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and fms-like tyrosine kinase-1 (flt-1)), non-receptor protein tyrosine kinases (eg, LCK, Src, Frk, Btk, Csk, AbI, Zap70, Fes / Fps, Fak, Jak, Ack and LIMK), growth factors Examples include receptor tyrosine kinases (eg, VEGF-R2, FGF-R, TEK, Akt kinase, etc.).

The compound of formula (I) may be an inhibitor of a protein kinase (eg, an inhibitor of a checkpoint kinase (eg, Chk1, Chk2, etc.)). Preferred compounds can exhibit IC ₅₀ values of less than about 25 μm (preferably from about 0.001 μm to about 1.0 μm, more preferably from about 0.001 μm to about 0.1 μm). The assay method is described in the examples described below.

The compounds of formula (I) can be inhibitors of protein kinases such as cyclin dependent kinases such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7 and CDK8. The compounds shown in Table 1 exhibited CDK2 inhibitory activity (IC ₅₀ ) of about 0.0001 μM to> about 5 μM. The assay method is described in the examples below.

式（Ｉ）の化合物は、増殖性疾患（例えば、癌）、自己免疫疾患、ウイルス性疾患、真菌性疾患、神経学的／神経変性障害、関節炎、炎症、抗増殖性疾患（例えば、眼の網膜症）、神経疾患、脱毛疾患および心臓血管疾患の治療において有用であり得る。これらの疾患および障害のうちの多くは、先に引用された米国特許第６，４１３，９７４号に列挙されており、これらは、本明細書中に参考として援用される。

The compounds of formula (I) are proliferative diseases (eg cancer), autoimmune diseases, viral diseases, fungal diseases, neurological / neurodegenerative disorders, arthritis, inflammation, antiproliferative diseases (eg ocular May be useful in the treatment of retinopathy), neurological diseases, hair loss diseases and cardiovascular diseases. Many of these diseases and disorders are listed in US Pat. No. 6,413,974, cited above, which are hereby incorporated by reference.

More specifically, the compound of formula (I) is a variety of cancers, including but not limited to: carcinoma (including bladder, breast, colon, kidney, liver, lung (including small cell lung cancer), non-small Cell lung cancer, including head and neck, esophagus, gallbladder, ovary, pancreas, stomach, neck, thyroid, prostate, and skin (including squamous cell carcinoma) cancer types);
Hematopoietic tumors of the lymphatic system (leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, ciliary cell lymphoma, mantle cell lymphoma, myeloma and Burkitt's lymphoma (including Burkett's lymphoma);
Hematopoietic tumors of direct bone marrow (including acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia);
Mesenchymal tumors (including fibrosarcoma and rhabdomyosarcoma);
Central and peripheral nervous system tumors (including astrocytoma, neuroblastoma, glioma and schwannomas); and other tumors (melanoma, seminoma, teratocarcinoma, osteosarcoma, pigment) It may be useful in the treatment of xeroderma pigmentosum, including keratocantoma, thyroid vesicular cancer and capage sarcoma.

  In general, because of the important role of CDK in the regulation of cell proliferation, inhibitors can act as reversible cytostatic agents, which can be used in any disease process with abnormal cell growth characteristics (eg, Benign prostatic hyperplasia, familial adenomatous polyposis, neurofibromatosis, atherosclerosis, pulmonary fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis after angioplasty or vascular surgery, hypertrophic scar formation , Inflammatory bowel disease, transplant rejection, endotoxic shock and fungal infection).

  The compounds of formula (I) also have Alzheimer's disease, as suggested by recent discoveries that CDK5 is involved in tau protein phosphorylation (J. Biochem, (1995) 117, 741-749). It can also be useful in treatment.

  Compounds of formula (I) can induce or inhibit apoptosis. Apoptotic responses are abnormal in various human diseases. The compounds of formula I may be used as modulators of apoptosis as cancer (including but not limited to the types of cancer described hereinabove), viral infections (herpes virus, poxvirus, Epstein-Barr virus, Treatment of, but not limited to, Sindbis virus and adenovirus, AIDS development in individuals infected with HIV, autoimmune diseases (systemic lupus erythematosus, autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis, inflammation Neurodegenerative disorders (Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa, spinal) Include but are not limited to muscle atrophy and cerebellar degeneration ), Myelodysplastic syndrome, aplastic anemia, myocardial infarction, stroke and reperfusion injury ischemic injury, arrhythmia, atherosclerosis, toxin-induced or alcohol-related liver disease, hematology Disorders (including but not limited to chronic anemia and aplastic anemia), musculoskeletal degenerative disorders (including but not limited to osteoporosis and arthritis), aspirin-sensitive nasal sinuses Useful in preventing inflammation, cystic fibrosis, multiple sclerosis, kidney disease and cancer pain.

  The compounds of formula (I) can modulate the level of cellular RNA and DNA synthesis as inhibitors of CDK. Accordingly, these factors are useful in the treatment of viral infections including but not limited to HIV, human papillomavirus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus.

  The compounds of formula (I) may also be useful in the chemoprevention of cancer. Chemoprevention inhibits the development of invasive cancers either by blocking the onset of mutational events or by blocking the progression of premalignant cells that have already been damaged, or Defined as inhibiting tumor recurrence.

  The compounds of formula (I) may also be useful in inhibiting tumor angiogenesis and metastasis.

  The compounds of formula (I) are also of other protein kinases (eg protein kinase C, her2, raf 1, MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor, PI3 kinase, wee1 kinase, Src, Abl). It can also act as an inhibitor, and thus can be effective in the treatment of diseases associated with other protein kinases.

  Another aspect of the invention is to provide a mammal (eg, human) having a disease or condition associated with CDK to a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable compound thereof. A method of treatment by administering a salt, solvate, ester or prodrug to this mammal.

  A preferred dosage is about 0.001 to 500 mg of a compound of formula (I) per kg body weight per day. A particularly preferred dosage is about 0.01 to 25 mg of compound of formula (I) or pharmaceutically acceptable salt, solvate, ester or prodrug of the compound per kg body weight per day.

  The compounds of the invention can also be administered (together or sequentially) in combination with one or more anticancer therapies (eg, radiation therapy) and / or one or more anticancer agents different from the compound of formula (I) ) May also be useful. The compound of the invention may be present in the same dosage unit as the anticancer agent or may be in a separate dosage unit.

  Another aspect of the invention is a method of treating one or more diseases associated with cyclin-dependent kinases, the method comprising an amount of a first compound (which is a compound of formula (I), or A pharmaceutically acceptable salt, solvate, ester or prodrug thereof); and an amount of at least one second compound, which is a different anticancer agent than the compound of formula (I) ) In a mammal in need of such treatment, wherein the amounts of the first and second compounds provide a therapeutic effect.

Non-limiting examples of suitable anticancer agents include cytostatics, cytotoxic agents (eg, including but not limited to DNA interacting agents (eg, cisplatin or doxorubicin)); taxanes (eg, Taxotere, taxol); topoisomerase II inhibitors (eg etoposide); topoisomerase I inhibitors (eg irinotecan (or CPT-11), camptostar or topotecan); tubulin interactors (eg paclitaxel, docetaxel or epothilone) ); Hormone agents (eg, tamoxifen); thymidylate synthase inhibitors (eg, 5-fluorouracil); antimetabolites (eg, methotrexat) )); Alkylating agents (e.g., temozolomide (Schering-Plough Corporation, Kenilworth, TEMODAR TM from New Jersey), cyclophosphamide); farnesyl protein transferase inhibitors ^{(e.g., SARASAR TM (4- [2- [} 4- [(11R) -3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo [5,6] cyclohepta [1,2-b] pyridin-11-yl-]-1-piperidinyl]- 2-oxoethyl] -1-piperidinecarboxamide or SCH 66336 from Schering-Plough Corporation, Kenilworth, New Jersey), tipifanib Zarnestra® or R115777 from Janssen Pharmaceuticals, L778,123 (farnesyl protein transferase inhibitor from Merck & Company, Whitehouse Station, New Jersey, BMS 21466 (BristolMrblysrq). Protein transferase inhibitors); signal transduction inhibitors (eg, Iressa (from Astra Zeneca Pharmaceuticals, England), Tarceva (EGFR kinase inhibitor), antibodies against EGFR (eg, C225) ^{, GLEEVEC TM (Novartis Pharmaceuticals, East} Hanover, C-abl kinase inhibitor from New Jersey); interferons (e.g., introns (Schering- Plow than Corporation), from Peg- Intron (Schering- Plough Corporation)); a combination of hormone therapy Aromatase combinations; ara-C, adriamycin, cytoxan and gemcitabine.

Other anticancer agents (also known as antitumor agents) include uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, piperobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin ( Streptozocin), dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin (leucovirin), oxaliplatin (Sanofi-Synthelabo Pharmaeuticals, ELOXATIN ^TM from France), pentostatin, Vinblastine, vincristine, vindesine, bleomycin , Dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide de Stilbestrol, testosterone, prednisone, fluoxymesterone, drmostanolone propionate, test lactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine , Medroxyprogesterone acetate, leupro , Flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, navelbene, anastrazol, razol Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, Herceptin, Bexar, Velcade, Zevalin, Trisenox, Xeloda, Vinorerubin, Porfimer, Pelmer Tax, Liposomar (Li posomal), thiotepa, altretamine, melphalan, trastuzumab, relozole, fulvestrant, ifosfomide, rituximab, C225, and campus.

  When formulated as a fixed dose, such combination products employ the dosage range of the compounds of the invention described herein and other pharmaceutically active or therapeutic agents in the dosage range. To do. For example, the CDC2 inhibitor olomucine has been found to synergize with known cytotoxic agents in inducing apoptosis (J. Cell Sci, (1995) 108, 2897). The compounds of formula (I) can also be administered sequentially with known anticancer or cytotoxic agents if a combination formulation is inappropriate. The present invention is not limited to the order of administration; the compound of formula (I) may be administered either before or after administration of the known anti-cancer or cytotoxic agent. For example, the cytotoxic activity of flavopiridol, a cyclin-dependent kinase inhibitor, is affected by the order of administration with anticancer agents. Cancer Research, (1997) 57, 3375. Such techniques are within the skills of those skilled in the art and physicians.

  Accordingly, in certain aspects, the present invention provides an amount of at least one compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, and an amount of one or more anti-drugs. Includes combinations comprising a cancer therapeutic agent and the anti-cancer agents listed above, wherein the amount of the compound / therapeutic agent provides the desired therapeutic effect.

  In a patient in need of inhibiting one or more checkpoint kinases, a method of inhibiting one or more checkpoint kinases comprises treating a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutical thereof Administering an acceptable salt, solvate, ester or prodrug to the patient.

  Another aspect of the present invention is to treat or progress a disease associated with one or more checkpoint kinases in a patient in need of treating or slowing the disease associated with one or more checkpoint kinases. A slowing method comprising administering a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. Is included.

  Yet another aspect of the invention is a method of treating one or more diseases associated with checkpoint kinases, the method comprising an amount of a first compound (which is a compound of formula (I), or A pharmaceutically acceptable salt, solvate, ester or prodrug thereof); and an amount of at least one second compound (the second compound is an anticancer agent) in need of such treatment. Administering to the mammal, wherein the amounts of the first and second compounds provide a therapeutic effect.

  Another aspect of the present invention is to treat or progress a disease associated with one or more checkpoint kinases in a patient in need of treating or slowing the disease associated with one or more checkpoint kinases. A method of slowing, comprising: a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I), or Administering a pharmaceutically acceptable salt, solvate, ester or prodrug in combination.

  In the above method, the checkpoint kinase to be inhibited can be Chk1 and / or Chk2.

  Another aspect of the invention is a method of inhibiting one or more tyrosine kinases in a patient in need of inhibiting one or more tyrosine kinases, the method comprising a therapeutically effective amount of at least one of Administering to the patient a compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

  Yet another aspect of the present invention relates to Akt kinase, Aurora kinase, and a patient in need of treating or slowing progression of a disease associated with one or more of Akt kinase, Aurora kinase, and tyrosine kinase. A method of treating or slowing progression of a disease associated with one or more of tyrosine kinases, comprising a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt thereof. Administering an acceptable salt, solvate, ester or prodrug.

  Another aspect of the invention is a method of treating one or more diseases associated with Akt kinase, Aurora kinase, and / or tyrosine kinase, the method comprising an amount of a first compound (which has the formula A compound of (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof); and an amount of at least one second compound (the second compound is an anticancer agent), Administering to a mammal in need of such treatment, wherein the amounts of the first and second compounds provide a therapeutic effect.

  Another aspect of the present invention is to provide Akt kinase, Aurora kinase, and tyrosine in a patient in need of treating or slowing progression of a disease associated with one or more of Akt kinase, Aurora kinase, and tyrosine kinase. A method for treating or slowing the progression of a disease associated with one or more of the kinases, comprising: treating a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable And a combination of at least one compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof).

  In the above method, the tyrosine kinase can be VEGFR, EGFR, HER2, SRC, JAK and / or TEK.

  Yet another aspect of the present invention is a method for treating or slowing a disease associated with Pim-1 kinase in a patient in need of treating or slowing the disease associated with Pim-1 kinase. Thus, the method comprises the step of administering a therapeutically effective amount of at least one compound of formula (I), or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

  Another aspect of the invention is a method of treating one or more diseases associated with Pim-1 kinase, the method comprising an amount of a first compound (which is a compound of formula (I), or A pharmaceutically acceptable salt, solvate, ester or prodrug thereof); and an amount of at least one second compound (the second compound is an anticancer agent) in need of such treatment. Administering to the mammal, wherein the amounts of the first and second compounds provide a therapeutic effect.

  Another aspect of the present invention is a method for treating or slowing a disease associated with Pim-1 kinase in a patient in need of treating or slowing the disease associated with Pim-1 kinase. The method comprises treating a therapeutically effective amount of a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I), or a pharmaceutically acceptable Salt, solvate, ester or prodrug in combination).

  The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. The exemplified pharmacological assays described later in this specification were performed with the compounds of the invention and their salts.

  The present invention also provides a pharmaceutical comprising at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof and at least one pharmaceutically acceptable carrier. He is also working on a creative composition.

  For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may contain from about 5 to about 95% active ingredient. Suitable solid carriers are known in the art (eg, magnesium carbonate, magnesium stearate, talc, sugar or lactose). Tablets, powders, cachets, and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of making various compositions are described in A. Gennaro (eds.), Remington's Pharmaceutical Sciences, 18th edition, (1990), Mack Publishing Co. , Easton, Pennsylvania.

  Liquid form preparations include solutions, suspensions and emulsions. Examples may include the addition of water or water-propylene glycol solutions for parenteral injection, or sweeteners and opacifiers for oral solutions, suspensions, and emulsions. Liquid form preparations may also include solutions for intranasal administration.

  Aerosol preparations suitable for inhalation may include solutions and powdered solids which may be combined with a pharmaceutically acceptable carrier such as a compressed inert gas such as nitrogen.

  Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions, and emulsions.

  The compounds of the present invention may also be deliverable transdermally. Transdermal compositions can take the form of creams, lotions, aerosols, and / or emulsions and can be included in matrix or reservoir type transdermal patches, as is conventionally done in the art for this purpose.

  The compounds of the present invention may also be delivered subcutaneously.

  Preferably, the compound is administered orally or intravenously.

  Preferably, the pharmaceutical preparation is in unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, eg, an effective amount to achieve the desired purpose.

  The amount of active compound in a unit dose of preparation may vary according to the specific application, or from about 1 mg to about 100 mg (preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg). Can be adjusted.

  The actual dosage used may vary depending on the requirements of the patient and the severity of the condition being treated. The determination of an appropriate dosing regimen for a particular condition is within the skill of the art. For convenience, the total daily dosage may be subdivided and may be administered in portions during the day if necessary.

  The amount and frequency of administration of the compounds of the invention and / or pharmaceutically acceptable salts thereof will depend on the attending physician's consideration of factors such as the age, condition, and size of the patient and the severity of the condition being treated. It is adjusted according to judgment. A generally recommended daily dosage regimen for oral administration ranges from about 1 mg / day to about 500 mg / day (preferably from about 1 mg / day to about 200 mg / day) in 2-4 divided doses. It can be.

  Another aspect of the invention is a pharmaceutically acceptable amount of a therapeutically effective amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or prodrug of this compound. Kit containing a suitable carrier, vehicle or diluent.

  Yet another aspect of the present invention provides an amount of at least one compound of formula (I) or a pharmaceutically acceptable salt, solvate, ester or prodrug of this compound and an amount of at least one anti-drug. A kit comprising a cancer treatment and / or an anti-cancer agent listed above, wherein the amount of the two or more components provides the desired therapeutic effect.

  The invention disclosed herein is illustrated by the following preparative examples and examples, which should not be construed to limit the scope of the present disclosure. Alternative mechanistic pathways and similar structures will be apparent to those skilled in the art.

Where NMR data is shown, ¹ H spectra are obtained on either Varian VXR-200 (200 MHz, ¹ H), Varian Gemini-300 (300 MHz) or XL-400 (400 MHz), Me ₄ Si As the ppm on the low magnetic field side, with proton number, multiplicity, and coupling constants shown in parentheses in hertz. Where LC / MS data is shown, the analysis was performed with an Applied Biosystems API-100 mass spectrometer and a Shimadzu SCL-10A LC column (Altech Platinum C18, 3 micron, 33 mm × 7 mm ID; gradient flow: 0 min-10% CH ₃ CN, 5 min _-95% CH 3 CN, 7 min _-95% CH 3 CN, 7.5 min _-10% CH 3 CN, 9 min - was performed using the stop). Retention times and observed parent ions are indicated.

The following solvents and reagents may be represented by their abbreviations in parentheses:
Thin layer chromatography: TLC
Dichloromethane: CH ₂ Cl ₂
Ethyl acetate: AcOEt or EtOAc
Methanol: MeOH
Trifluoroacetic acid: TFA
Triethylamine: Et ₃ N or TEA
Butoxycarbonyl: n-Boc or Boc
Nuclear magnetic resonance spectroscopy: NMR
Liquid chromatography mass spectrometry: LCMS
High resolution mass spectrometry: HRMS
Milliliters: mL
Mmol: mmol
Microliter: μl
Gram: g
Milligrams: mg
Room temperature or rt (ambient): about 25 ° C
Dimethoxyethane: DME
In general, the compounds described in this invention can be prepared through the general route described in Scheme 1 shown below.

(Preparation Examples and Examples)
(Preparation Examples)
Preparation Example 1

ジエチルマロンイミデート二塩酸塩（２３．１ｇ、０．１０ｍｏｌ）のＥｔ_２Ｏ中の攪拌懸濁液に、０℃で、水性の飽和したＫ_２ＣＯ_３（２００ｍＬ）の溶液を加えた。この混合物を、Ｎ_２下で０℃で５分間攪拌し、その後、分液ろうと中で単離させ、そして水性の部分をＥｔ_２Ｏ（２×２００ｍＬ）で抽出した。合わせたエーテル抽出物をＮａ_２ＳＯ_４で乾燥させ、ろ過し、そして溶媒をエバポレートした。生じた無色の油状物（１４．９ｇ）を、９９％Ｎ_２Ｈ_４．Ｈ_２Ｏ（４．７１ｇ、９４．３ｍｍｏｌ）のＥｔＯＨ（４５ｍＬ）中の攪拌した沸騰溶液に少しずつ加え、この混合物を１０分間攪拌し、そして４℃で１６時間保った。溶媒をエバポレートし、そして残渣を、シリカゲルのカラムクロマトグラフィー（ＭｅＯＨ中の４：１のＣＨ_２Ｃｌ_２／７Ｎ ＮＨ_３を溶出液として使用）によって精製した。薄い黄色の固体（４．４０ｇ、４８％）を得た。

To a stirred suspension of diethylmalonimidate dihydrochloride (23.1 g, 0.10 mol) in Et ₂ O at 0 ° C. was added a solution of aqueous saturated K ₂ CO ₃ (200 mL). The mixture was stirred at 0 ° C. under N ₂ for 5 minutes, then isolated in a separatory funnel and the aqueous portion was extracted with Et ₂ O (2 × 200 mL). The combined ether extracts were dried over Na ₂ SO ₄ , filtered and the solvent was evaporated. The resulting colorless oil (14.9 g) was purified by 99% N ₂ H ₄ . H ₂ O (4.71 g, 94.3 mmol) was added in portions to a stirred boiling solution in EtOH (45 mL) and the mixture was stirred for 10 minutes and kept at 4 ° C. for 16 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel (4: 1 CH ₂ Cl ₂ / 7N NH ₃ in MeOH was used as eluent). A pale yellow solid (4.40 g, 48%) was obtained.

  Preparation Example 2

調製実施例１からの生成物（９８０ｍｇ、１０．０ｍｍｏｌ）とベンゾイル酢酸エチル（２．２０ｇ、１１．５ｍｍｏｌ）のＡｃＯＨ（１５ｍＬ）中の混合物を攪拌し、そしてＮ_２下で５時間還流した。この混合物を２５℃まで冷却し、固体をろ過し、フィルター上でＡｃＯＨ（２０ｍＬ）、Ｅｔ_２Ｏ（４０ｍＬ）で洗浄し、そして真空中で乾燥させた。クリーム色の固体（９３０、３５％）を得た。Ｍｐ＞３００℃。ＬＣ−ＭＳ：２６９［Ｍ＋Ｈ］。

A mixture of the product from Preparative Example 1 (980 mg, 10.0 mmol) and ethyl benzoyl acetate (2.20 g, 11.5 mmol) in AcOH (15 mL) was stirred and refluxed under N ₂ for 5 hours. The mixture was cooled to 25 ° C., the solid was filtered, washed on the filter with AcOH (20 mL), Et ₂ O (40 mL) and dried in vacuo. A cream colored solid (930, 35%) was obtained. Mp> 300 ° C. LC-MS: 269 [M + H].

Preparation Example 3
By essentially the same procedure as described in Preparative Example 2, from the ethyl acetoacetate and the product from Preparative Example 1, the compound shown below:

を調製した。

Was prepared.

  Preparation Example 4

調製実施例２からの生成物（４４０ｍｇ、１．６４ｍｍｏｌ）、Ｎ，Ｎ−ジメチルアニリン（０．６３ｍＬ）およびＰＯＣｌ_３（５．０ｍＬ）の混合物を、Ｎ_２下で２５℃で４日間攪拌した。溶媒をエバポレートし、そして残渣を、シリカゲルのカラムクロマトグラフィー（２：１のＣＨ_２Ｃｌ_２／ＥｔＯＡｃを溶出液として使用）によって精製した。薄い黄色の固体（２２５ｍｇ、４８％）を得た。ＬＣ−ＭＳ：２８７［Ｍ＋］。

A mixture of the product from Preparative Example 2 (440 mg, 1.64 mmol), N, N-dimethylaniline (0.63 mL) and POCl ₃ (5.0 mL) was stirred at 25 ° C. under N ₂ for 4 days. . The solvent was evaporated and the residue was purified by column chromatography on silica gel using 2: 1 CH ₂ Cl ₂ / EtOAc as eluent. A pale yellow solid (225 mg, 48%) was obtained. LC-MS: 287 [M +].

Preparation Example 5
Following essentially the same procedure as described in Preparative Example 4, the compound shown below:

を調製した。

Was prepared.

  Preparation Example 6

ＮＢＳ（６２ｍｇ、０．３５ｍｍｏｌ）の無水ＣＨ_３ＣＮ（３ｍＬ）中の溶液を、調製実施例４からの生成物（１００ｍｇ、０．３５ｍｍｏｌ）の無水ＣＨ_３ＣＮ（３ｍＬ）およびＣＨ_２Ｃｌ_２（６ｍＬ）中の攪拌溶液にＮ_２下で加えた。この混合物を２時間攪拌し、溶媒をエバポレートし、そして残渣を、シリカゲルのカラムクロマトグラフィー（３：２のＣＨ_２Ｃｌ_２／ＥｔＯＡｃを溶出液として使用）によって精製した。薄い黄色の固体（５２ｍｇ、４１％）を得た。ＬＣ−ＭＳ：３６７［Ｍ＋Ｈ］。

A solution of NBS (62 mg, 0.35 mmol) in anhydrous CH ₃ CN (3 mL) was added to the product from Preparative Example 4 (100 mg, 0.35 mmol) in anhydrous CH ₃ CN (3 mL) and CH ₂ Cl ₂ ( It was added under _{N 2} to a stirred solution of 6 mL). The mixture was stirred for 2 hours, the solvent was evaporated and the residue was purified by column chromatography on silica gel using 3: 2 CH ₂ Cl ₂ / EtOAc as eluent. A pale yellow solid (52 mg, 41%) was obtained. LC-MS: 367 [M + H].

  Preparation Example 7

調製実施例４からの生成物（５０ｍｇ、０．１７ｍｍｏｌ）、２．０Ｍ ＮＨ_３の２−プロパノール（２．０ｍＬ）および水性の濃ＮＨ_４ＯＨ（０．２ｍＬ）中の混合物を、密閉型圧力容器内で６０℃で２０時間攪拌した。溶媒をエバポレートし、そして残渣を、シリカゲルのカラムクロマトグラフィー（８：１のＣＨ_２Ｃｌ_２／ＭｅＯＨを溶出液として使用）によって精製した。薄い黄色の固体（３０ｍｇ、６４％）を得た。Ｍｐ＝２５８〜２６０℃。ＬＣ−ＭＳ：２６８［Ｍ＋Ｈ］。

A mixture of the product from Preparative Example 4 (50 mg, 0.17 mmol), 2.0 M NH ₃ in 2-propanol (2.0 mL) and aqueous concentrated NH ₄ OH (0.2 mL) was sealed pressure. The mixture was stirred at 60 ° C. for 20 hours in the container. The solvent was evaporated and the residue was purified by column chromatography on silica gel (using 8: 1 CH ₂ Cl ₂ / MeOH as eluent). A pale yellow solid (30 mg, 64%) was obtained. Mp = 258-260 ° C. LC-MS: 268 [M + H].

Preparation Example 8
The compound shown below was prepared by essentially the same procedure as described in Preparative Example 7.

調製実施例９

Preparation Example 9

調製実施例２からの生成物（１００ｍｇ、０．３７ｍｍｏｌ）とＫＯＨ（２００ｍｇ）とのＥｔＯＨ（５ｍＬ）およびＨ_２Ｏ（１ｍＬ）中の混合物を攪拌し、そしてＮ_２下で８時間還流した。溶媒をエバポレートし、そして残渣を、シリカゲルのカラムクロマトグラフィー（５：１のＣＨ_２Ｃｌ_２／ＭｅＯＨを溶出液として使用）によって精製した。薄い黄色の固体（６ｍｇ、７％）を得た。Ｍｐ＝１７５〜１７７℃。ＬＣ−ＭＳ：２２７［Ｍ＋Ｈ］。

A mixture of the product from Preparative Example 2 (100 mg, 0.37 mmol) and KOH (200 mg) in EtOH (5 mL) and H ₂ O (1 mL) was stirred and refluxed under N ₂ for 8 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel (using 5: 1 CH ₂ Cl ₂ / MeOH as eluent). A pale yellow solid (6 mg, 7%) was obtained. Mp = 175-177 ° C. LC-MS: 227 [M + H].

Preparation Examples 10-11
The compound shown below was prepared by essentially the same procedure as described in Preparative Example 9.

調製実施例１２

Preparation Example 12

調製実施例５からの生成物（２２４ｍｇ、１．００ｍｍｏｌ）とナトリウムチオメトキシド（７７ｍｇ、１．１０ｍｍｏｌ）のＴＨＦ（５ｍＬ）中の混合物を、２５℃でＮ_２下で２０時間攪拌した。溶媒をエバポレートし、そして残渣をシリカゲルのカラムクロマトグラフィー（１０：１のＣＨ_２Ｃｌ_２／ＭｅＯＨを溶出液として使用）によって精製した。白色固体（２１０ｍｇ、８９％）を得た。ＬＣ−ＭＳ：２３７［Ｍ＋Ｈ］。

A mixture of the product from Preparative Example 5 (224 mg, 1.00 mmol) and sodium thiomethoxide (77 mg, 1.10 mmol) in THF (5 mL) was stirred at 25 ° C. under N ₂ for 20 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel (using 10: 1 CH ₂ Cl ₂ / MeOH as eluent). A white solid (210 mg, 89%) was obtained. LC-MS: 237 [M + H].

(Example)
Example 1:

調製実施例２からの生成物（１００ｍｇ、０．３７ｍｍｏｌ）とＫＯＨ（２００ｍｇ）とのＥｔＯＨ（５ｍＬ）およびＨ_２Ｏ（１ｍＬ）中の混合物を攪拌し、そしてＮ_２下で８時間還流した。溶媒をエバポレートし、そして残渣を、シリカゲルのカラムクロマトグラフィー（５：１のＣＨ_２Ｃｌ_２／ＭｅＯＨを溶出液として使用）によって精製した。薄い黄色の固体（６ｍｇ、７％）を得た。Ｍｐ＝１７５〜１７７℃。ＬＣ−ＭＳ：２２７［Ｍ＋Ｈ］。

A mixture of the product from Preparative Example 2 (100 mg, 0.37 mmol) and KOH (200 mg) in EtOH (5 mL) and H ₂ O (1 mL) was stirred and refluxed under N ₂ for 8 hours. The solvent was evaporated and the residue was purified by column chromatography on silica gel (using 5: 1 CH ₂ Cl ₂ / MeOH as eluent). A pale yellow solid (6 mg, 7%) was obtained. Mp = 175-177 ° C. LC-MS: 227 [M + H].

Example 2:
The following compounds were prepared by essentially the same procedure as described in Example 1.

実施例３：
実施例１で述べた手順と本質的に同じ手順で、下に示す化合物を調製した。

Example 3:
The following compounds were prepared by essentially the same procedure as described in Example 1.

（アッセイ）
ＣＨＫ１ ＳＰＡアッセイ
バキュロウイルスの発現系において発現される組換えＨｉｓ−ＣＨＫ１を酵素源として、そしてＣＤＣ２５Ｃを基にしたビオチン化（ｂｉｏｔｉｎｙｌａｔｅｄ）ペプチドを基質（ビオチン−ＲＳＧＬＹＲＳＰＳＭＰＥＮＬＮＲＰＲ）として利用するインビトロのアッセイを開発した。

(Assay)
CHK1 SPA Assay An in vitro assay utilizing recombinant His-CHK1 expressed in baculovirus expression system as an enzyme source and a biotinylated peptide based on CDC25C as a substrate (biotin-RSGLYRSP S MPENLNRPR) developed.

Materials and reagents:
1) CDC25C Ser 216 C-term biotinylated peptide substrate (25 mg), stored at -20 ° C., custom synthesized by Research Genetics: Biotin-RSGLYRSPSMPENLNRPR 2595.4 MW
2) His-CHK1 In House lot P976, 235 ug / mL, stored at −80 ° C. 3) D-PBS (without CaCl and MgCl): GIBCO, Cat. # 14190-144
4) SPA beads: Amersham, Cat. # SPQ0032: Add 500 mg / vial 10 ml D-PBS to 500 mg SPA beads to make a working concentration of 50 mg / ml. Store at 4 ° C. Use within 2 weeks after hydration.
5) 96-well white microplate with GF / B filter joined: Packard, Cat. # 6005177
6) Top Seal-A 96-well adhesive film: Perkin Elmer, Cat. # 6005185
7) 96-well non-binding white polystyrene plate: Corning, Cat. # 6005177
8) MgCl ₂ : Sigma, Cat. # M-8266
9) DTT: Promega, Cat. # V3155
10) ATP, stored at 4 ° C .: Sigma, Cat. # A-5394
11) γ ³³ P-ATP, 1000 to 3000 Ci / mMol: Amersham, Cat. # AH9968
12) NaCl: Fisher Scientific, Cat. # BP358-212
13) H ₃ PO ₄ 85% Fisher, Cat. # A242-500
14) Tris-HCL pH 8.0: Bio-Whittaker, Cat. # 16-015V
15) Staurosporine, 100 ug: CALBIOCHEM, Cat. # 569397
16) Hypere cell culture grade water, 500 mL: HyClone, Cat. # SH305299.02.

Reaction mixture:
1) Kinase buffer: 50 mM Tris pH 8.0; 10 mM MgCl ₂ ; 1 mM DTT
2) His-CHK1, In House Lot P976, MW about 30 KDa, stored at -80 ° C.
6 nM is required to obtain a positive control of about 5,000 CPM. For one plate (100 rxn): Dilute 8 uL of 235 μg / mL (7.83 uM) in 2 mL of kinase buffer. This makes a 31 nM mixture. Add 20 μL per well. This brings the final reaction concentration to 6 nM.
3) CDC25C biotinylated peptide CDC25C is diluted to a 1 mg / mL (385 uM) stock and stored at -20 ° C. For one plate (100 rxn): Dilute 10 uL of 1 mg / mL peptide stock in 2 ml kinase buffer. This gives a mixture of 1.925 uM. Add 20 μL per reaction. This brings the final reaction concentration to 385 nM.
4) ATP mixture For one plate (100 rxn): Dilute 10 μL of 1 mM ATP (unlabeled) stock and 2 μL of fresh P33-ATP (20 μCi) in 5 ml kinase buffer. This gives a 2 uM ATP (unlabeled) solution; add 50 μl per well to start the reaction. Since the final volume is 100 ul per reaction, the final reaction concentration is 1 μM ATP (unlabeled) and 0.2 μCi per reaction.
5) Stop solution:
Per plate: Add 10 mL of Wash Buffer 2 (2M NaCl 1% H ₃ PO ₄ ): 1 mL of a slurry of SPA beads (50 mg); add 100 μL per well.
6) Wash buffer 1: 2M NaCl
7) Wash buffer 2: 2M NaCl, 1% H ₃ PO ₄
Assay procedure:

１）化合物を、水／１０％ＤＭＳＯ中に所望する濃度まで希釈−これによって、反応物中の最終ＤＭＳＯ濃度が１％となる。１つの反応につき１０μｌを適切なウェルに分配する。１０μＬの１０％ＤＭＳＯを陽性コントロール（ＣＨＫ１＋ＣＤＣ２５Ｃ＋ＡＴＰ）と陰性コントロール（ＣＨＫ１＋ＡＴＰのみ）のウェルに加える。
２）酵素を氷上で解凍−−酵素を、キナーゼ緩衝液中（反応混合物を参照されたい）に適切な濃度に希釈し、そして各ウェルに２０μｌを分配する。
３）ビオチン化基質を氷上で解凍し、そしてキナーゼ緩衝液（反応混合物を参照されたい）中に希釈する。陰性コントロールのウェル以外は、１ウェルにつき２０μｌ加える。その代わりにこ陰性コントロールのウェルには２０μＬのキナーゼ緩衝液を加える。
４）ＡＴＰ（非標識）およびＰ３３−ＡＴＰをキナーゼ緩衝液（反応混合物を参照されたい）中に希釈する。１ウェルにつき５０μＬを加えて、反応を開始する。
５）この反応を室温で２時間持続させる。
６）１００ｕＬのＳＰＡビーズ／停止溶液（反応混合物を参照されたい）を加えて反応を停止させ、そして採取する前に１５分間インキュベートする。
７）真空ろ過装置（Ｐａｒｋａｒｄプレートハーベスター）内に空のＰａｃｋａｒｄ ＧＦ／Ｂフィルタープレートを置き、そしてこのシステムを湿らせるために２００ｍＬの水を吸引する。
８）この空のプレートを取り出し、そしてＰａｃｋａｒｄ ＧＦ／Ｂフィルタープレート中に入れる。
９）反応物をフィルタープレートを通して吸引する。
１０）洗浄：各洗浄につき２００ｍｌ；２Ｍ ＮａＣｌで１回；２Ｍ ＮａＣｌ／１％Ｈ_３ＰＯ_４で１回
１１）フィルタープレートを１５分間乾燥させる。
１２）フィルタープレートの上部にトップシール−Ａの９６ウェル粘着フィルムを置く。
１３）Ｔｏｐ Ｃｏｕｎｔ内でフィルタープレートを処理する
設定：データモード：ＣＰＭ
放射線核種：マニュアルＳＰＡ：Ｐ３３
シンチレーター：液体／プラスチック
エネルギー範囲：低い
ＣＤＫ２アッセイ：
バキュロウイスル構築：サイクリンＡおよびサイクリンＥを、アミノ末端にＧｌｕＴＡＧ配列（ＥＹＭＰＭＥ）を付加して、ＰＣＲによってｐＦＡＳＴＢＡＣ（Ｉｎｖｉｔｒｏｇｅｎ）内にクローニングし、抗−ＧｌｕＴＡＧ親和カラムでの精製を可能にした。発現されたタンパク質はおおよそ４６ｋＤａ（サイクリンＥ）および５０ｋＤａ（サイクリンＡ）の大きさであった。ＣＤＫ２もまた、カルボキシ末端（ＹＤＶＰＤＹＡＳ）に赤血球凝集素（ｈａｅｍａｇｌｕｔｉｎｉｎ）エピトープタグを付加し、ＰＣＲによってｐＦＡＳＴＢＡＣ内にクローニングした。発現されたタンパク質はおおよそ３４ｋＤａのサイズであった。

1) Dilute the compound in water / 10% DMSO to the desired concentration-this will give a final DMSO concentration in the reaction of 1%. Dispense 10 μl per reaction into appropriate wells. Add 10 μL of 10% DMSO to wells of positive control (CHK1 + CDC25C + ATP) and negative control (CHK1 + ATP only).
2) Thaw enzyme on ice--Dilute enzyme to appropriate concentration in kinase buffer (see reaction mixture) and dispense 20 μl to each well.
3) Thaw biotinylated substrate on ice and dilute in kinase buffer (see reaction mixture). Add 20 μl per well except for negative control wells. Instead, add 20 μL of kinase buffer to this negative control well.
4) Dilute ATP (unlabeled) and P33-ATP in kinase buffer (see reaction mixture). Add 50 μL per well to start the reaction.
5) The reaction is continued for 2 hours at room temperature.
6) Stop the reaction by adding 100 uL SPA beads / stop solution (see reaction mixture) and incubate for 15 minutes before harvesting.
7) Place an empty Packard GF / B filter plate in a vacuum filtration apparatus (Parcard plate harvester) and aspirate 200 mL of water to wet the system.
8) Remove the empty plate and place it in a Packard GF / B filter plate.
9) Aspirate the reaction through the filter plate.
10) Washing: 200 ml for each wash; 1 time with 2M NaCl; 1 time with 2M NaCl / 1% H ₃ PO ₄ 11) Dry the filter plate for 15 minutes.
12) Place top seal-A 96 well adhesive film on top of filter plate.
13) Setting to process the filter plate in Top Count: Data mode: CPM
Radionuclide: Manual SPA: P33
Scintillator: liquid / plastic Energy range: low CDK2 assay:
Baculoisul construction: Cyclin A and cyclin E were cloned into pFASTBAC (Invitrogen) by PCR with the addition of a GluTAG sequence (EYMPME) at the amino terminus, allowing purification on an anti-GluTAG affinity column. The expressed protein was approximately 46 kDa (cyclin E) and 50 kDa (cyclin A). CDK2 was also cloned into pFASTBAC by PCR with a haemagglutinin epitope tag at the carboxy terminus (YDVPDYAS). The expressed protein was approximately 34 kDa in size.

Enzyme production: Recombinant baculoviruses expressing cyclin A, cyclin E and CDK2 were infected into SF9 cells at a multiplicity of infection (MOI) of 48 hours. Cells were harvested by centrifugation for 10 minutes at 1000 RPM. A cyclin (E or A) containing pellet is combined with a pellet of CDK2 containing cells and lysis buffer (50 mM Tris pH 8.0, 0.5% NP40, 1 mM DTT and protease) 5 times the volume of the pellet on ice. / Solution in phosphatase inhibitor (including Roche Diagnostics GmbH, Mannheim, Germany) for 30 minutes. The mixture was stirred for 30-60 minutes to promote the formation of cyclin-CDK2 complex. The mixed lysate was then spun down at 15000 RPM for 10 minutes and the supernatant retained. The cyclin-CDK2 complex was then captured using 5 ml anti-GluTAG beads (for 1 liter SF9 cells). Bound beads were washed 3 times in lysis buffer. The protein was competitively eluted with a lysis buffer containing 100-200 μg / mL GluTAG peptide. The eluate was dialyzed overnight in 2 liters of kinase buffer (containing 50 mM Tris pH 8.0, 1 mM DTT, 10 mM MgCl ₂ , 100 uM sodium orthovanadate and 20% glycerol). The enzyme was stored as aliquots at -70 ° C.

In vitro kinase assay: CDK2 kinase assay (either cyclin A or cyclin E dependent) was performed in 96 well plates with low protein binding (Corning Inc, Corning, New York). The enzyme was diluted in kinase buffer (containing 50 mM Tris pH 8.0, 10 mM MgCl ₂ , 1 mM DTT, and 0.1 mM sodium orthovanadate) to a final concentration of 50 μg / ml. The substrate used in these reactions was a biotinylated peptide derived from Histone H1 (from Amersham, UK). The substrate was thawed on ice and diluted to 2 μM in kinase buffer. The compound was diluted at the desired concentration in 10% DMSO. For testing, for each kinase reaction, 20 μl of 50 μg / ml enzyme solution (1 μg enzyme) and 20 μl of 1 μM substrate solution were mixed and combined with 10 μl of diluted compound in each well. The kinase reaction was initiated by the addition of 50 μl 4 μM ATP and 1 μCi 33P-ATP (from Amersham, UK). The reaction was allowed to run for 1 hour at room temperature. Add 200 μl stop buffer (containing 0.1% Triton X-100, 1 mM ATP, 5 mM EDTA and 5 mg / ml streptavidin coated SPA beads (from Amersham, UK) over 15 minutes This stopped the reaction. The SPA beads were then captured on 96 well GF / B filter plates (Packard / Perkin Elmer Life Sciences) using a Filtermate universal harvester (Packard / Perkin Elmer Life Sciences). Non-specific signals were removed by washing the beads twice with 2M NaCl and then twice with 2M NaCl containing 1% phosphate. The radioactive signal was then measured using a TopCount 96-well liquid scintillation counter (from Packard / Perkin Elmer Life Sciences).

IC ₅₀ determination: Dose-response curves were plotted from inhibition data obtained from 8 serial dilutions of inhibitory compounds, each done in duplicate. Compound concentration was plotted against% kinase activity calculated by dividing the CPM of the treated sample by the CPM of the untreated sample. Thereafter, in order to calculate an IC ₅₀ value, this dose - response curves, fitted to a standard S-shaped curve and IC ₅₀ values were obtained by nonlinear regression analysis. The IC ₅₀ values for selected compounds of the present invention thus obtained are shown in Table 1 above. These kinase activities were obtained using the above assay.

  As demonstrated by the assay values, the compounds of the invention may exhibit excellent Chk1 inhibitory properties.

  Although the present invention has been described in connection with the specific embodiments described above, numerous alternatives, modifications, and other variations thereof will be apparent to those skilled in the art. All such alternatives, modifications and variations are intended to be within the spirit and scope of the present invention.

Claims (75)

Structural formula (I):

Or a pharmaceutically acceptable salt, solvate, ester or prodrug of the compound of formula (I), comprising:
here:
R ² is H, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocycloalkyl, trifluoromethyl, halo, —CN, —OCF ₃ , —CO ₂ R ⁸ , -CONR ⁸ R ⁹ , -OR ^8a , -SR ⁸ , -SO ₂ R ⁸ , -SO ₂ NR ⁸ R ⁹ , -NR ⁸ SO ₂ R ⁹ , -NR ⁸ COR ⁹ and -NR ⁸ CONR ⁸ R Selected from the group consisting of ⁹ ;
R ³ is haloalkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —NR ⁵ R ^8a , — _{^{NR 8 COR 9, -NR 8 SO}} 2 R 9, -COR 8, -CO 2 R 8, -CONR 8 R 9, -CH 2 OR 8, -OR 8b, -SR 8, -SO 2 R 8, - S (O ₂ ) NR ⁸ R ⁹ , —S (O ₂ ) aryl, —S (O ₂ ) heteroaryl, —C (O) NR ⁸ R ⁹ , —C (O) OR ⁹ , —C (O) Aryl, —C (O) heteroaryl, — (CHR ⁵ ) _n -aryl, — (CHR ⁵ ) _n -heteroaryl,

Wherein the alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, as indicated above for R ³ , Each of heteroaryl, heteroarylalkyl and their heterocyclic moieties may be unsubstituted or optionally substituted with one or more moieties, which may be the same or different, each moiety Is H, halo, alkyl, trifluoromethyl, —OR ⁸ , —NR ⁸ R ⁹ , —SR ⁸ , —SO ₂ R ⁹ , —CN, —SO ₂ NR ⁸ R ⁹ , —CF ₃ and —NO _2. Independently selected from the group consisting of;
R ⁴ is H, halo, haloalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,- ^{NR 8 R 9, -NR 8 COR} 9, -NR 8 SO 2 R 9, -COR 8, -CO 2 R 8, -CONR 8 R 9, -CH 2 OR 8, -OR 8, -SR 8, - _{^{SO 2 R 8, -S (O}} 2) NR 8 R 9, -S (O 2) aryl, -S _{(O 2)} ^{heteroaryl, -C (O) OR 9,} -C (O) aryl, -C (O) heteroaryl, - ^(CHR _{5) n} - aryl, - ^(CHR _{5) n} - heteroaryl,

Wherein the alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, as indicated above for R ⁴ , Each of heteroaryl, heteroarylalkyl and their heterocyclic moieties may be unsubstituted or optionally substituted with one or more moieties, which may be the same or different, each moiety Is H, halo, alkyl, trifluoromethyl, —OR ⁸ , —NR ⁸ R ⁹ , —SR ⁸ , —SO ₂ R ⁹ , —CN, —SO ₂ NR ⁸ R ⁹ , —CF ₃ and —NO _2. Independently selected from the group consisting of;
R ^a is H, halo, haloalkyl, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl,- ^{NR 8 R 9, -NR 8 COR} 9, -NR 8 SO 2 R 9, -COR 8, -CO 2 R 8, -CONR 8 R 9, -CH 2 OR 8, -OR 8, -SR 8, - _{^{SO 2 R 8, -S (O}} 2) NR 8 R 9, -S (O 2) aryl, -S _{(O 2)} ^{heteroaryl, -C (O) OR 9,} -C (O) aryl, -C (O) heteroaryl, - ^(CHR _{5) n} - aryl, - ^(CHR _{5) n} - heteroaryl,

Wherein the alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, alkenylalkyl, alkynylalkyl, heterocyclyl, heterocyclylalkyl, as indicated above for R ^a , Each of heteroaryl, heteroarylalkyl and their heterocyclic moieties may be unsubstituted or optionally substituted with one or more moieties, which may be the same or different, each moiety Is H, halo, alkyl, trifluoromethyl, —OR ⁸ , —NR ⁸ R ⁹ , —SR ⁸ , —SO ₂ R ⁹ , —CN, —SO ₂ NR ⁸ R ⁹ , —CF ₃ and —NO _2. Independently selected from the group consisting of;
R ⁵ is selected from the group consisting of H, alkyl, aryl or cycloalkyl;
R ⁶ is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein the alkyl, alkenyl, aryl, aryl Each of the alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups is unsubstituted or optionally substituted with one or more moieties, which may be the same or different. the resulting, each portion, halo, alkyl, aryl, cycloalkyl, _{^{heterocyclylalkyl, -CF 3, -OCF 3, -CN}} , -OR 5, -NR 5 R 10, -C (R 5 R 11) p -R ^{9, -N} (R 5) Boc _{^{- (CR 5 R 11) p}} OR 5, -C (O 2) R 5, -C (O) R 5, -C (O) NR 5 R 10, -SO 3 H, -SR 10, -S ( _{^{O 2) R 7, -S (}} O 2) NR 5 R 10, -N (R 5) S (O 2) R 7, -N (R 5) C (O) R 7 and -N ^(R 5) Independently selected from the group consisting of C (O) NR ⁵ R ¹⁰ ;
R ⁷ is selected from the group consisting of alkyl, cycloalkyl, aryl, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl, wherein said alkyl, cycloalkyl, heteroarylalkyl, aryl Each of, arylalkenyl, heteroaryl, arylalkyl, heteroarylalkyl, heteroarylalkenyl and heterocyclyl is optionally substituted with one or more moieties which may be unsubstituted or the same or different independently may be substituted, each portion is halo, alkyl, aryl, _{^{cycloalkyl, CF 3, OCF 3, CN}} , -OR 5, -NR 5 R 10, -CH 2 OR 5, -C (O 2 ^{) R 5, -C (O)} NR _{^{R 10, -C (O) R}} 5, -SR 10, -S (O 2) R 10, -S (O 2) NR 5 R 10, -N (R 5) S (O 2) R 10, - ^{N (R 5) C (O} ) R 10 and ^{-N (R 5) C (O} ) independently from the group consisting of NR ^{5 R 10} is selected;
R ⁸ is H, —OR ⁶ , —NR ⁵ R ⁶ , —C (O) NR ⁵ R ¹⁰ , —S (O ₂ ) NR ⁵ R ¹⁰ , —C (O) R ⁷ , —C (= N _{-CN) -NH 2, -C (=} NH) -NHR 5, ^{_{heterocyclyl, -S (O 2) R 7}} ,

—OR ¹⁰ , —CF ₃ , alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein the alkyl, alkenyl, aryl Each of the, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups is optionally substituted with one or more moieties that may be unsubstituted or the same or different. Each moiety may be substituted, each halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, —CF ₃ , —OCF ₃ , —CN, —OR ⁵ , —NR ⁵ R ¹⁰ , —C (R ⁵ R ¹¹ ) _p -R ^9, -N (R _{^{5) Boc, - (CR 5}} R 11) p OR 5, -C (O 2) R 5, -C (O) R 5, -C (O) NR 5 R 10, -SO 3 H, -SR 10 _{^{, -S (O 2) R 7}} , -S (O 2) NR 5 R 10, -N (R 5) S (O 2) R 7, -N (R 5) C (O) R 7 and -N Independently selected from the group consisting of (R ⁵ ) C (O) NR ⁵ R ¹⁰ ;
R ^{8a is, -OR 6, -NR 5 R 6} , -C (O) NR 5 R 10, -S (O 2) NR 5 R 10, -C (O) R 7, -C (= N-CN _{) -NH 2, -C (= NH} ) -NHR 5, ^{_{heterocyclyl, -S (O 2) R 7}} ,

, —OR ¹⁰ , —CF ₃ , alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein the alkyl, alkenyl, Each of the aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups is optionally substituted with one or more moieties that may be unsubstituted or the same or different. And each moiety is halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, —CF ₃ , —OCF ₃ , —CN, —OR ⁵ , —NR ⁵ R ¹⁰ , —C (R ⁵ R ¹¹ ). _p -R ^9, -N ( _{^{R 5) Boc, - (CR}} 5 R 11) p OR 5, -C (O 2) R 5, -C (O) R 5, -C (O) NR 5 R 10, -SO 3 H, -SR ¹⁰ , —S (O ₂ ) R ⁷ , —S (O ₂ ) NR ⁵ R ¹⁰ , —N (R ⁵ ) S (O ₂ ) R ⁷ , —N (R ⁵ ) C (O) R ⁷ and — Independently selected from the group consisting of N (R ⁵ ) C (O) NR ⁵ R ¹⁰ ;
R ^{8b is, -OR 6, -NR 5 R 6} , -C (O) NR 5 R 10, -S (O 2) NR 5 R 10, -C (O) R 7, -C (= N-CN _{) -NH 2, -C (= NH} ) -NHR 5, ^{_{heterocyclyl, -S (O 2) R 7}} ,

, —OR ¹⁰ , —CF ₃ , alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein the alkyl, alkenyl, aryl, Each of the arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups is unsubstituted or optionally substituted with one or more moieties that may be the same or different are obtained, each portion, halo, alkyl, aryl, cycloalkyl, _{^{heterocyclylalkyl, -CF 3, -OCF 3, -CN}} , -OR 5, -NR 5 R 10, -C (R 5 R 11) p - ^{R 9, -N (R 5)} B _{^{c, - (CR 5 R 11}} ) p OR 5, -C (O 2) R 5, -C (O) R 5, -C (O) NR 5 R 10, -SO 3 H, -SR 10, - _{^{S (O 2) R 7,}} -S (O 2) NR 5 R 10, -N (R 5) S (O 2) R 7, -N (R 5) C (O) R 7 and -N (R ⁵ ) independently selected from the group consisting of C (O) NR ⁵ R ¹⁰ ;
R ⁹ is H, —OR ⁶ , —NR ⁵ R ⁶ , —C (O) NR ⁵ R ¹⁰ , —S (O ₂ ) NR ⁵ R ¹⁰ , —C (O) R ⁷ , —C (= N _{-CN) -NH 2, -C (=} NH) -NHR 5, ^{_{heterocyclyl, -S (O 2) R 7}} ,

, —OR ¹⁰ , —CF ₃ , alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein the alkyl, alkenyl, Each of the aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups is optionally substituted with one or more moieties that may be unsubstituted or the same or different. And each moiety is halo, alkyl, aryl, cycloalkyl, heterocyclylalkyl, —CF ₃ , —OCF ₃ , —CN, —OR ⁵ , —NR ⁵ R ¹⁰ , —C (R ⁵ R ¹¹ ). _p -R ^9, -N ( _{^{R 5) Boc, - (CR}} 5 R 11) p OR 5, -C (O 2) R 5, -C (O) R 5, -C (O) NR 5 R 10, -SO 3 H, -SR ¹⁰ , —S (O ₂ ) R ⁷ , —S (O ₂ ) NR ⁵ R ¹⁰ , —N (R ⁵ ) S (O ₂ ) R ⁷ , —N (R ⁵ ) C (O) R ⁷ and — Independently selected from the group consisting of N (R ⁵ ) C (O) NR ⁵ R ¹⁰ ;
R ¹⁰ is selected from the group consisting of H, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, wherein the alkyl, alkenyl, aryl, aryl Each of the alkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl groups is unsubstituted or optionally substituted with one or more moieties, which may be the same or different. the resulting, each portion, halo, alkyl, aryl, cycloalkyl, _{^{heterocyclylalkyl, -CF 3, -OCF 3, -CN}} , -OR 5, -NR 5 R 11, -C (R 5 R 11) p -R ^9, -N ^(R 5) Bo _{^{, - (CR 5 R 11)}} p OR 5, -C (O 2) R 5, -C (O) R 5, -C (O) NR 5 R 11, -SO 3 H, -SR 11, -S _{^{(O 2) R 7, -S}} (O 2) NR 5 R 11, -N (R 5) S (O 2) R 7, -N (R 5) C (O) R 7 and -N ^{(R 5} ) Independently selected from the group consisting of C (O) NR ⁵ R ¹¹ ;
Or optionally (i) the partial ^-NR 5 or ^{R 5} and ^{R 11} in ^{R 11,} or (ii) ^{R 5} and ^{R 6} in the moiety ^-NR 5 within ^{R 6} are joined together, cyclo Alkyl or heterocyclyl moieties may be formed, each of the cycloalkyl or heterocyclyl moieties being unsubstituted or optionally substituted independently with one or more R ⁹ groups;
R ¹¹ is H, halo or alkyl;
m is 0-4;
n is 1-4; and p is 1-4.
However:
(A) When R ² is defined as above, at least one of R ³ , R ⁴ and R ^a is —NH ₂ , —OH, alkoxy, alkylthio, halo, alkynyl, alkenylalkyl and alkynylalkyl. Or (b) when R ³ , R ⁴ and R ^a are defined as above, R ² is alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, alkenyl, alkynyl, A compound, which is a condition that it is selected from the group consisting of alkenylalkyl, alkynylalkyl, trifluoromethyl, —OCF ₃ , —OR ^8a , —SR ⁸ and —NR ⁸ CONR ⁸ R ⁹ . The compound of claim 1, wherein R ² is H. The compound of claim 1, wherein R ² is Br. The compound of claim 1, wherein R ² is selected from the group consisting of Cl, -SH, -CN, alkyl, alkenyl, alkynyl, and cyclopropyl. R ² is cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, —OCF ₃ , —CO ₂ R ⁸ , —CONR ⁸ R ⁹ , —OR ^8a , —SR ⁸ , —SO ₂ R ⁸ , —SO ₂ The compound of claim 1, selected from the group consisting of NR ⁸ R ⁹ , —NR ⁸ SO ₂ R ⁹ , —NR ⁸ COR ⁹ and —NR ⁸ CONR ⁸ R ⁹ . The compound of claim 1, wherein R ³ is benzyl. The compound of claim 1, wherein R ³ is methyl. R ³ is aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, —S (O ₂ ) aryl, —S (O ₂ ) heteroaryl, —C (O) aryl, -C (O) heteroaryl, - ^(CHR _{5) n} - aryl, - ^(CHR _{5) n} - heteroaryl,

Wherein the aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl and their heterocyclic moieties as shown above for R ³ are selected from the group consisting of Each may be unsubstituted or optionally substituted with one or more moieties, which may be the same or different, each moiety being H, halo, alkyl, trifluoromethyl,- ^{oR 8, -NR 8 R 9,} -SR 8, -SO 2 R 9, -CN, -SO 2 NR 8 R 9, are independently selected from the group consisting of -CF ₃ and -NO _2, claim 1. The compound according to 1. R ³ is haloalkyl, alkenyl, alkynyl, alkenylalkyl, alkynylalkyl, —NR ⁵ R ^8a , —NR ⁸ COR ⁹ , —NR ⁸ SO ₂ R ⁹ , —COR ⁸ , —CO ₂ R ⁸ , —CONR ⁸ R ⁹ , —CH ₂ OR ⁸ , —OR ^{8 b} , —SR ⁸ , —SO ₂ R ⁸ , —S (O ₂ ) NR ⁸ R ⁹ , wherein the alkyl, alkenyl, alkynyl, alkenyl Each of alkyl, alkynylalkyl may be unsubstituted or optionally substituted with one or more moieties, which may be the same or different, each moiety being H, halo, alkyl, tri- ^{fluoromethyl, -OR 8, -NR 8 R 9} , -SR 8, -SO 2 R 9, -CN, -SO 2 NR 8 R 9, or -CF ₃ and -NO ₂ Made independently selected from the group A compound according to claim 1. The compound of claim 1, wherein R ³ is alkoxy. The compound of claim 1, wherein R ³ is alkylthio. R ³ is

The compound of claim 1, selected from the group consisting of: R ³ may be the same or different and each is 1 to 3 aryl or heteroaryl groups independently selected from the group consisting of phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups The compound of claim 1 which is substituted aryl. R ³ may be the same or different and each is 1 to 3 aryl or heteroaryl groups independently selected from the group consisting of phenyl, pyridyl, thiophenyl, furanyl and thiazolo groups 2. The compound of claim 1, which is a substituted heteroaryl. R ³ is heteroaryl, heteroarylalkyl, is selected from the group consisting of heterocyclyl and heterocyclylalkyl A compound according to claim 1. The compound of claim 1, wherein R ⁴ is H. R ⁴ is, Cl, Br, -OH, -SH, alkyl, alkenyl, alkynyl, selected from the group consisting of haloalkyl and cyclopropyl A compound according to claim 1. The compound of claim 1, wherein R ⁴ is —NH ₂ . The compound of claim 1, wherein R ⁴ is —OH. The compound of claim 1, wherein R ⁴ is alkoxy. The compound of claim 1, wherein R ⁴ is alkylthio. The compound of claim 1, wherein R ⁴ is halo. The compound of claim 1, wherein R ^a is —NH ₂ . The compound of claim 1, wherein R ^a is —OH. The compound of claim 1, wherein R ^a is alkoxy. 2. A compound according to claim 1 wherein R ^<a> is alkylthio. The compound of claim 1, wherein R ^a is halo. The compound of claim 1, wherein R ^a is Cl. The compound of claim 1, wherein R ⁵ is H. The compound of claim 1, wherein n is 1. The compound of claim 1, wherein p is 1. formula:

Wherein R ² = R ⁴ = H;
A compound wherein R ³ is aryl; and R ^a is an amine. formula:

Wherein R ² = R ⁴ = H;
A compound wherein R ³ is phenyl; and R ^a is an amine. formula:

Wherein R ² = R ⁴ = H;
A compound wherein R ³ is aryl; and R ^a is —NH ₂ . formula:

Wherein R ² is halo;
R ³ is aryl;
A compound wherein R ⁴ is H; and R ^a is an amine. formula:

Wherein R ² is bromo;
R ³ is aryl;
A compound wherein R ⁴ is H; and R ^a is an amine. formula:

Wherein R ² is bromo;
R ³ is phenyl;
A compound wherein R ⁴ is H; and R ^a is an amine. formula:

Wherein R ² is bromo;
R ³ is phenyl;
A compound wherein R ⁴ is H; and R ^a is —NH ₂ . formula:

Wherein R ² = R ⁴ = H;
A compound wherein R ³ is aryl; and R ^a is —OH. formula:

Wherein R ² = R ⁴ = H;
A compound wherein R ³ is phenyl; and R ^a is —OH.

A compound selected from the group consisting of: or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. 2. A compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, in purified and isolated form. A pharmaceutical comprising a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate or ester thereof in combination with at least one pharmaceutically acceptable carrier. Composition. 44. The pharmaceutical composition of claim 43, further comprising one or more anticancer agents different from the compound of claim 1. The one or more anticancer agents are cytostatic, cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-11, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, 5FU, Temozolomide, cyclophosphamide, SCH 66336, R115777, L778, 123, BMS 214466, Iressa, Tarceva, antibodies against EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan , Chlorambucil, pipbloman, triethylenemelamine, triethylenethiophosphoramine, busulfan, potassium Lumustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin , Mitramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethynylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drmostanolone propionate, test lactone, megestrol acetate, methyl Prednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotriani Sen, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, naberben, CPT- 11, anastrazol, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, herceptin, bexal, velcade, zevalin, trisenox, xeloda, vinorelbine, porfimer, erbitux, liposomal, thiotepa, altretamine, melphalan , Trastuzumab, relozole, fulvestrant, exemestane, ifosfamide, ritsuki Mab, is selected from the group consisting of C225 and campuses, pharmaceutical composition according to claim 44. Use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof for the manufacture of a medicament for inhibiting a cyclin dependent kinase. At least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate thereof, for the manufacture of a medicament for treating one or more diseases by inhibiting cyclin dependent kinases, Use of esters or prodrugs. (I) at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvent thereof for the manufacture of a medicament for treating one or more diseases by inhibiting cyclin dependent kinases. A use of at least one second compound, wherein the second compound is a different anticancer agent than the compound of claim 1; 49. Use according to any one of claims 46, 47 or 48, wherein the cyclin dependent kinase is CDK1. 49. Use according to any one of claims 46, 47 or 48, wherein the cyclin dependent kinase is CDK2. The disease is bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, head and neck cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, Skin cancer, including cervical cancer, thyroid cancer, prostate cancer, and squamous cell carcinoma;
Leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, ciliary cell lymphoma, mantle cell lymphoma, myeloma and Burkitt Lymphoma;
Acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia;
Fibrosarcoma, rhabdomyosarcoma;
Astrocytoma, neuroblastoma, glioma and schwannoma;
49. Either of the claims 47 or 48, selected from the group consisting of melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratophyte cell tumor, thyroid follicular carcinoma and Kaposi's sarcoma Use according to 1. 49. Use according to any one of claims 46, 47 or 48, further comprising radiation therapy. The anticancer agent is a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-11, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, 5FU, temozolomide Famide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies against EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil , Triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine Lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN ^TM, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin , Doxorubicin, epirubicin, idarubicin, mitramycin, deoxycoformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethynylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, test lactone, Megestrol acetate, methylprednisolone, methyltestosterone, pre Nizolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitoxantrone, mitoxantrone, Levamisole, navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, droloxafine, hexamethylmelamine, avastin, herceptin, bexal, velcade, zevaline, trisenox, xeloda, vinorelbine, porfimer, erbitux, liposomal Thiotepa, Altretamine, Melphalan, Trastuzumab, Rerosol, Fulvestrane , Exemestane, Ifosufomido, rituximab, is selected from the group consisting of C225 and campus use of claim 48. Use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof for the manufacture of a medicament for inhibiting checkpoints. At least one compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or alleviating progression of a disease associated with one or more checkpoint kinases, Use of solvates, esters or prodrugs. (I) at least one compound of claim 1, or a pharmaceutically acceptable salt, solvate thereof, for the manufacture of a medicament for treating one or more diseases by inhibiting checkpoint kinases. Products, esters or prodrugs; and (ii) an amount of at least one second compound, the second compound being an anticancer agent. At least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate thereof, for the manufacture of a medicament for treating a disease or slowing progression by inhibiting checkpoints, Use of esters or prodrugs. 58. Use according to any one of claims 54, 55, 56 or 57, wherein the checkpoint kinase is Chk1. 58. Use according to any one of claims 54, 55, 56 or 57, wherein the checkpoint kinase is Chk2. 2. At least one compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for inhibiting a kinase selected from the group consisting of Akt kinase, Aurora kinase and tyrosine. , Use of esters or prodrugs. 2. At least one compound according to claim 1 for the manufacture of a medicament for treating or slowing progression of a disease by inhibiting a kinase selected from the group consisting of Akt kinase, Aurora kinase and tyrosine kinase. Or use of a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. The use of (i) at least one claim 1 for the manufacture of a medicament for treating one or more diseases by inhibiting a kinase selected from the group consisting of Akt kinase, Aurora kinase and tyrosine kinase. The use of a compound or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; and (ii) an amount of at least one second compound, the second compound being an anticancer agent. Akt kinase, Aurora kinase and tyrosine kinase in a patient in need of treating or slowing progression of one or more diseases by inhibiting a kinase selected from the group consisting of Akt kinase, Aurora kinase and tyrosine kinase At least one pharmaceutically acceptable carrier for the manufacture of a medicament for treating or slowing the progression of one or more diseases by inhibiting a kinase selected from the group consisting of Use of a pharmaceutical composition comprising one compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof in combination. 64. Use according to any one of claims 60, 61, 62 or 63, wherein the tyrosine kinase is selected from the group consisting of VEGFR, EGFR, HER2, SRC, JAK and TEK. 64. Use according to any one of claims 60, 61, 62 or 63, wherein the tyrosine kinase is VEGFR. 64. Use according to any one of claims 60, 61, 62 or 63, wherein the tyrosine kinase is EGFR. Use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof for the manufacture of a medicament for inhibiting Pim-1 kinase. At least one compound according to claim 1, or a pharmaceutically acceptable salt, solvate thereof, for the manufacture of a medicament for treating or slowing the progression of a disease by inhibiting Pim-1. Use of esters or prodrugs. (I) at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvent thereof for the manufacture of a medicament for treating one or more diseases by inhibiting Pim-1 kinase. Use of a hydrate, ester or prodrug; and (ii) an amount of at least one second compound, the second compound being an anticancer agent. At least one pharmaceutically acceptable carrier for the manufacture of a medicament for treating or alleviating progression of one or more diseases by inhibiting Pim-1 kinase; and at least one claim 1. Or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof. Use of at least one compound according to claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof for the manufacture of a medicament for treating cancer. The cancer is bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, head and neck cancer, esophageal cancer, gallbladder cancer, ovarian cancer, pancreatic cancer, stomach cancer, Skin cancer, including cervical cancer, thyroid cancer, prostate cancer, and squamous cell carcinoma;
Leukemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, ciliary cell lymphoma, mantle cell lymphoma, myeloma and Burkitt lymphoma;
Acute and chronic myeloid leukemia, myelodysplastic syndrome and promyelocytic leukemia;
Fibrosarcoma, rhabdomyosarcoma;
Head and neck, mantle cell lymphoma, myeloma;
Astrocytoma, neuroblastoma, glioma and schwannoma;
72. Use according to claim 71, selected from the group consisting of melanoma, seminoma, teratocarcinoma, osteosarcoma, xeroderma pigmentosum, keratophyte cell carcinoma, thyroid follicular carcinoma and Kaposi's sarcoma. (Ii) an amount for the manufacture of a medicament for treating cancer; (i) at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof; Use of at least one second compound, wherein the second compound is an anticancer agent. 74. Use according to claim 73, further comprising radiation therapy. The anticancer agent is a cytostatic, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilone, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide 36, CH66 R115777, L778,123, BMS 214662, Iressa, Tarceva, EGFR antibody, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, piperobroman, triethylenemelamine, tri Ethylenethiophosphoramine, busulfan, carmustine, lomustine, strep Tozosin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, mitramycin, deoxy Coformycin, mitomycin-C, L-asparaginase, teniposide 17α-ethynylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, drmostanolone propionate, test lactone, megestrol acetate, methylprednisolone, methyltestosterone, Prednisolone, triamcinolone, chlorotrianicene, hydroxyprogesterone, Aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, goserelin, cisplatin, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, naberbene, anastrazol, letrazole, capecitabine , Leloxafin, Droloxafine, Hexamethylmelamine, Avastin, Herceptin, Bexal, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomar, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerosol, Fulvestrant, Exemestane, fulvestrant, ifosfamide, rituximab, C225 and can It is selected from the group consisting of scan Use according to claim 73.